MEDISCH-GENETISCH CENTRUM ZUID-WEST NEDERLAND - MGC
MGC-Bulletin, Nr. 51, September 2014
In dit nummer:
Onderwijs voor promovendi .......................... 2
Coördinatie en redactie:
M. Nivard/I. Braxhoven
PhD Teaching Programme Committee ......... 3
e-mail: nivard@lumc.nl
MGC Promovendi Workshop 2015 ................ 3
: 071-5269605/69601
Promoties ....................................................... 3
Nieuwe medewerkers ..................................... 4
Lezingen/symposia ........................................ 6
Sectie 'DNA herstel-mechanismen' ............... 7
Sectie ‘Lysosomal Storage Diseases’ .......... 7
Verkregen subsidies ...................................... 7
Personalia/Prijzen .......................................... 8
Overige mededelingen ................................... 8
MGC-Bulletin no. 52 ....................................... 9
Program 24th MGC Symposium .................... 10
Abstracts 24th MGC Symposium .................. 11
De MGC bestuurders en hun instituten ....... 19
Andere instituten/groepen binnen het MGC 19
Het MGC secretariaat .................................... 19
De uitreiking van de Prinses Beatrix Spierfonds
wetenschapsprijs aan Silvère van der Maarel.
Foto: Frank van Beek
Het Centrum is een initiatief van het
Universitair Medisch Centrum Rotterdam en het
Leids Universitair Medisch Centrum
Onderwijs voor promovendi
Het
aanbod
van
cursussen
voor
promovendi in het LUMC is tegenwoordig
online beschikbaar. Deze informatie is te
vinden op http://albinusnet.lumc.nl/home/.
A course "From Molecular Pathogenesis
to Targeted Therapy " will be organized
from 27 – 31 October 2014 in Leiden. The
aim of this course is to give an overview of
intracellular signalling processes that are
activated by hormones, cytokines and
growth factors, as well as state-of-the-art
technology
used
to
study
signal
transduction in vivo and in vitro. Teaching
will occur by state-of-the-art lectures and
interactive tutorial. For more info see
www.medgencentre.nl.
A course "Live cell and super resolution
imaging" will be organized from 27-31
October 2014 in Rotterdam. The aim of the
course is to provide a comprehensive
introduction to the field of translational
cancer research. This five day course
consists of lecture sessions in the morning
and practical sessions in the afternoon; on
some days also evening sessions with a
dinner. In the final session on Friday
afternoon participants will present and
discuss the results of their practical work.
For more info see www.medgencentre.nl
A course on "Safely working in the lab”
will be given in December in Leiden. The
following points will be addressed: safe
microbiological techniques; radionuclides;
carcinogenic agents; blood, viruses;
radiation. The course is also open for other
new personal of the MGC. The course will
be given twice a year depending on the
interest
in
collaboration
with
the
Department VSM of the LUMC. Apply
through
the
MGC
web
site:
www.medgencentre.nl or for people from
the LUMC via ‘bedrijfsopleidingen’.
From our sister school Molecular Medicine
the following courses are available:
 Photoshop
and
Illustrator
CS6
workshop:
September-October,
a
hands-on full day workshop on the
MGC-Bulletin no. 51; September 2014
2
programs Photoshop and Illustrator CS6.
These programs are used for image
enhancement and drawing high quality
graphs, tables and other figures
 Indesign CS6 Workshop: September –
October, a half-day Workshop on Adobe
Indesign CS6.
 Biomedical Research Techniques: 13
– 17 October. A basic five-day course on
several lab techniques. The program
covers: Day 1: primers and probes,
sequencing, SNP analysis, methylation;
Day 2: RNA, RNA expression arrays, RT
PCR, siRNA, data mining; Day 3: site
visit DNA/RNA labs; proteomes, mass
spectrometry; Day 4: ELISA, cytotoxicity,
flow cytometry, phage antibody display;
microscopy; Day 5: Applied molecular
imaging: MRI, CR, nuclear, optical in
vivo and site visit proteomic labs.
 Translational Imaging Workshop by
AMIE: from mouse to man: 11-14
November. The aim of this 4-day
workshop is to give a broad introduction
into
preclinical
and
translational
molecular imaging techniques and their
applications in biology and medicine.
 SNP Course: 17-21 November. An
annual 5-day course on SNP and
complex diseases, including hands-on
computer practicals. Basic knowledge of
the central molecular biological is
required.
For detailed information & registration info
www.molmed.nl
Courses organized by Boerhaave CME:
 Advanced Genetic & Genomic Data
analysis: 20 – 22 October. This course
in genetic association analysis includes
now highly relevant topics such as the
analysis for multidisciplinary research
with novel omics datasets. It covers
analysis and practical issues of rare
variants detected by next generation
sequencing and gene expression
analysis. Participants need to bring their
own laptop.
 Survival Analysis: 3-7 November.
Survival analysis is the study of the
distribution of life times, i.e. the times
from an initiating event (birth, diagnosis,
start of treatment) to some terminal
event (relapse, death). During the
course different types of censored data
will be introduced and techniques for
estimating the survival function by
employing both parametric and nonparametric methods will be illustrated.
Multiplicative
hazards
regression
models,
testing
and
inference
techniques will be studied in great
details. Special aspects as timedependent
covariates
effects,
stratification, time and prediction will be
introduced. Techniques to be used to
assess the validity of the hazard
regression model will be discussed.
 Meta Analysis: 5-7 November. Metaanalyse
is
een
kwantitatieve
samenvatting van een aantal studies
binnen
een
systematisch
literatuuronderzoek.
Met
deze
driedaagse cursus krijgt u een overzicht
van de principes van systematisch
literatuuronderzoek en de statistische
methoden die voor meta-analyse
worden
gebruikt.
De
statistische
analyses worden geoefend met het
programma STATA. Na deze cursus
kunt u artikelen over literatuuronderzoek
doorgronden en op kwaliteit beoordelen
en kunt u zelf een (eenvoudige) metaanalyse uitvoeren.
For detailed information & registration:
www.boerhaavenet.nl.
PhD
Teaching
Committee
The MGC-PhD student workshop is a 4day event organized every year by PhD
students for PhD students.
During this workshop PhD students get the
chance to:

- exchange knowledge in an informal
and relaxed way, through posters and
presentations

- build their own network during social
events and free time
The workshop is meant for PhD students
who are doing their research in one of the
MGC departments. The attendance to the
workshop is part of the PhD program and
PhD students should attend at least three
times during their PhD.
Foto: Martí Quevedo
De prijswinnaressen tijdens de workshop:
Valliveti Subramanyam Reddy (beste
poster) en Risha Smeding (beste lezing)
Programme
Since 2011 the MGC has a newly formed
PhD Teaching Programme Committee.
Members of the committee are: Raymond
Poot and Kerstin Wendt of the Erasmus
MC and Dorien Peters, Harry Vrieling and
Madeleine Nivard of the LUMC. The
committee will focus primarily on evaluation
of the existing course program and will
advise on new courses or teaching
activities
(Contact
email
address:
nivard@lumc.nl).
MGC Promovendi Workshop 2015
The 21st MGC-PhD workshop was held in
Münster, Germany and was a big success.
The 22nd workshop will be held in June
2015. Venue is not known yet. For more
information see www.mgcworkshop.nl.
MGC-Bulletin no. 51; September 2014
3
Promoties
Anika Vaarhorst is op 13 mei in Leiden
gepromoveerd op het proefschrift "Genetic
and metabolomic approaches for coronary
heart disease risk rediction". Promotor:
Prof. P. Slagboom; co-promotor: Dr. B.
Heijmans.
Ingrid Verhaart is op 20 mei in Leiden
gepromoveerd
op
het
proefschrift
"Optimising antisense oligonucleotidemediated exon skipping for Duchenne
muscular dystrophy". Promotor: Prof. G.
van Ommen; co-promotor: Dr. A. AartsmaRus.
Arjan Theil is op 4 juni gepromoveerd in
Rotterdam op het proefschrift "Functional
analysis of TTDA: from human to mouse –
big impact of a small protein". Promotor:
Prof. J. Hoeijmakers; co-promotor: Dr. W.
Vermeulen.
Petra Schwertman is op 6 juni
gepromoveerd in Rotterdam op het
proefschrift "Quitination in the UV-induced
DNA damage response; from proteomics to
patient". Promotor: Prof. J. Hoeijmakers;
co-promotoren: Dr. W. Vermeulen en Dr. J.
Marteijn.
Juna de Vries is op 10 juni in Rotterdam
gepromoveerd op het proefschrift "Natural
course, effects of enzyme therapy and
prognostic factors in adults with Pompe
disease". Promotor: Prof. van der Ploeg.
Erwin Brosens is op 17 juni in Rotterdam
gepromoveerd op het proefschrift "Foregut
development: an act of balance. Next
generation sequencing and copy number
variation profiling in EA/TEF". Promotor:
Prof. D. Tibboel.
Javier Ramirez Martin is op 17 juni in
Leiden gepromoveerd op het proefschrift
"The cell-type specific role of FcyRIIb in
immune-complex-mediated
inflammatory
diseases". Promotor: Prof. S. van der
Maarel; co-promotor: Dr. J. Verbeek.
Carine van Capelle is op 18 juni in
Rotterdam
gepromoveerd
op
het
proefschrift "Children with Pompe disease:
clinical characteristics, peculiar features
and effects of enzyme replacement
therapy". Promotor: Prof. van der Ploeg.
Linda van den Berg is op 24 juni in
Rotterdam
gepromoveerd
op
het
proefschrift "The musculoskeletal system in
Pompe disease". Promotor: Prof. van der
Ploeg.
Celine de Esch is op 25 juni in Rotterdam
gepromoveerd
op
het
proefschrift
"Therapeutic targets and translational
endpoints in fragile X syndrome". Promotor:
Prof. R. Willemsen.
Joris Deelen is op 25 juni Cum Laude
gepromoveerd in Leiden op het proefschrift
"Genetic and biomarker studies of human
longevity". Promotoren: Prof. P. Slagboom
en Prof. R. Westendorp; co-promotor: Dr.
M. Beekman.
Anine Stam is op 26 juni in Leiden
gepromoveerd op het proefschrift "Genetics
of migraine and related syndromes".
Promotoren: Prof.M. Ferrari en Prof. A. van
den Maagdenberg; co-promotor: Dr. G.
Terwindt.
MGC-Bulletin no. 51; September 2014
4
Ralph Stadhouders is in Rotterdam op 12
september
gepromoveerd
op
het
proefschrift
"Transcription
factors,
chromatin
looping
and
cellular
differentiation; guiding cells towards
adulthood". Promotor: Prof. F. Grosveld;
co-promotor: Dr. E. Soler.
Klaas Hermans is op 16 september
gepromoveerd in Rotterdam op het
proefschrift "Reflections on the mechanism
of DNA mismatch repair". Promotor: Prof.
R. Kanaar; co-promotor: Dr. J. Lebbink.
Thomas Clapes is op 17 september
gepromoveerd in Rotterdam op het
proefschrift
"Role
of
CLASP2
in
hematopoietic stem cells". Promotor: Prof.
E. Dzierzak; co-promotor: Dr. C. Robin.
Kasper Derks hoopt op 22 oktober in
Rotterdam te promoveren op het
proefschrift "The DNA damage respons:
nucleic acid regulation in sequence".
Promotoren: Prof. J. Hoeijmakers en Prof.
B. van der Horst; co-promotor: Dr. J.
Pothof.
Sherif Shawky Abdou hoopt op 28
oktober in Rotterdam te promoveren op het
proefschrift "Development of nanoparticles
based assays for the direct detection of
unamplified nucleic acids in clinical
specimens". Promotor: Prof. F. Grosveld;
co-promotor: Dr. H. Azzay.
Özge Aydin hoopt in Rotterdam op 29
oktober te promoveren op het proefschrift
"Chromatin remodeling in the UV-induced
DNA damage response". Promotor: Prof. J.
Hoeijmakers; co-promotoren: Dr. W.
Vermeulen en Dr. H. Lans.
Maikel Wouters hoopt op 12 december in
Rotterdam te promoveren op het
proefschrift "MicroRNAs, the DNA damage
response and cancer". Promotor: Prof. J.
Hoeijmakers; co-promotor: Dr. J. Pothof.
Nieuwe medewerkers
Bij de afdeling Anatomie & Embryologie
(Leiden):
Anneloes Dummer is onlangs als OIO
gestart op onze afdeling.
Oleh Halaidych is ook als OIO begonnen
op een project on 'Phenotypic biophysical
measurements of disease (hPSC-derived)
cardiomyocytes (force, Ca, electrophysiology) and vascular smooth muscle celles
derived from human pluripotent stem cells
and the development of new bioassays.
de 'pulmonary vascular development in
congenital diaphragmatic hemia".
Bij de afdeling Biochemie (Rotterdam):
Ayestha Sijma is per september als OIO
gestart in de groep van Peter Verrijzer. Zij
gaat werken aan het NWO project
"Polycombing chromatin and beyond" to
understand
the
role
of
protein
(de)ubiquitylation by Polycomb group
(PcG)
proteins
in
balancing
cell
differentiation
and
proliferation.
In de groep van Tokameh Mahmoudi zijn
twee nieuwe OIO's gestart: Matteusz
Stoszo per 1 februari en Enrico Ne per 15
juni.
Bij de afdeling Klinische Genetica
(Rotterdam):
Tjakko van Ham started on May 1st as a
researcher (Marie Curie & ZonMW VENI
project "Immune responses in neurodegenerative diseases: Protection or progression?") on the role of the immune system in
brain disease. Immune cells are implicated
in nearly all brain diseases, but their role is
poorly understood. He uses zebrafish as a
model system to investigate how immune
cells contribute to brain disease or tissue
reapir and to figure out how this is
controlled molecularly using functional
genetics and small molecule screening.
Nynke Oosterhof started on July 1st as
OIO in the group of Tjakko van Ham. She
is interested in using zebrafish to study the
role of the immune system in brain
diseases and applying new technologies
including intravital imaging an RNAseq the
brain's immune cells, such as microglia,
and what role these cells play in disease.
Helen de Boer is per 15 april 2014 als
analist begonnen.
Laura Kuil is per 1 september gestart als
OIO en zal ook gaan werken aan Zebravis
neurodegeneratie.
Kyra Smit is per 15 september als OIO
gestart en werkt aan "Micro RNAs in uveal
melanoma).
Bij de afdeling Genetica (Rotterdam):
On September 1st, Jana Slyskova started
working as a postdoc in the lab of Wim
Vermeulen, funded by an EMBO fellowship. She will be screening for synthetic
genetic interactions in colorectal cancer.
Bij de afdeling Humane Genetica (Leiden):
Remko Goossens (groepsleider Silvère
van der Maarel) is per 1 september
werkzaam als OIO op het project ‘De rol
van een nieuwe chromatine modifier in de
pathogenese van FSHD’, gesubsidieerd
door het Prinses Beatrix Spierfonds.
Haoyu Wu (groepsleider Silvère van der
Maarel / Lucia Clemens Daxinger) werkt
sinds 1 september (onder de directe leiding
van Lucia) als OIO aan epigenetische
modificaties in de hersenen in relatie tot
mentale retardatie en andere neuroontwikkelingsstoornissen.
Rob van den Akker (groepsleider Silvère
van der Maarel) werkt als researchanalist
aan de opheldering van het epigenetische
mechanisme dat ten grondslag ligt aan
FSHD en maakt hierbij gebruik van
humane cellulaire en muismodel systemen.
Bij
de
afdeling
Kindergeneeskunde
(Rotterdam):
In de groep van Robbert Rottier is Evelien
Eenjes aan een OIO traject begonnen. In
diezelfde groep is Daphne Mous al eerder
van start gegaan met haar onderzoek naar
MGC-Bulletin no. 51; September 2014
5
Bij de afdeling Moleculaire Epidemiologie
(Leiden):
Niels van den Berg is per 1 september
aangenomen als OIO op het project
"Genes, Germs and Resources. The role of
the family in survival since 1812". Voor dit
interdisciplinaire
project
werken
sociaaleconomische historici van de
Radboud Universiteit Nijmegen samen met
epidemiologen van de sectie Moleculaire
Epidemiologie van het LUMC. Er wordt
onderzoek gedaan naar de invloed van
familiale factoren op vroege sterfte van
zuigelingen
en
kinderen
en
op
uitzonderlijke langlevendheid in Nederland
van 1812 tot 2015. Dit gebeurt vanuit een
innovatief interpretatiekader waarin de
gelijktijdige invloeden worden bekeken van
de genetische factoren (genes), de
ziekteomgeving
(germs)
en
de
sociaaleconomische en culturele aspecten
van het individu (resources). Het effect van
deze factoren wordt onderzocht met behulp
van een multi-generationele benadering
waarbij families worden gevolgd over een
periode van twee eeuwen. Het doel daarbij
is om de wisselwerking op te sporen tussen
enerzijds de biologische en genetische
invloeden die familieleden met elkaar delen
en anderzijds de sociaal-structurele
component, bijvoorbeeld de sociale en
economische groep die
gezinnen en
families gemeen hebben. Deze interactie
wordt
bestudeerd
binnen
de
epidemiologische context van de 19e en
20ste eeuw. Niels gaat o.a. grote historische
databestanden analyseren waarbij de
levensduur van verschillende groepen
individuen over generaties heen gevolgd
en vergeleken wordt.
Bij de afdeling Toxicogenetica/Humane
Genetica (Leiden):
Remco Derr is per Juni begonnen als
analist in de groep van Harry Vrieling. Hij
gaat samen met Giel Hendriks werken aan
de verdere validatie van de ToxTracker
assay en het creëren van nieuwe reporter
systemen voor verschillende cellulaire
stress response pathways.
As of September Jenny Singh has started
as a PhD student on an ERC-funded
project in the group of Haico van Attikum.
She will identify and characterise
chromatin-modifying enzymes involved in
the DNA damage response.
In mei is Yvonne Tiersma analiste in het
lab van Niels de Wind. Zij werkt onder
begeleiding van Mark Drost en in
samenwerking met labs uit Nederland,
Denemarken en de Verenigde Staten aan
een project gefinancierd door de National
Institute of Health. Doel van het project is
de ontwikkeling van een gestandaardiseerde procedure om de pathogeniciteit te
bepalen van varianten in mismatch
herstellende genen in patiënten verdacht
van Lynch syndroom.
Lezingen/symposia
NKI Seminars are given at the NKI,
Plesmanlaan 121, Amsterdam:
Location: Piet Borst Auditorium, 11.00 hrs.
September 12: Emile Voest "The spleen as
a key regulator of chemoresistance".
September 19: Simon Boulton "Genome
stability and the control of homologous
recombination".
September 24: André Nussenzweig
"Determinants of genome integrity in
BRCA1/2 mutant cells" (NB: 14:00 hrs)
September 26: Wim Vermeulen "Lesionstalled
transcription
and
chromatin
remodeling".
October 3: Erik Sahai "Imaging invasion
and therapy failure".
October 17: Adrian Bird "CpG as a
genomic signalling module".
October 28: Zena Werb "New insights into
microenvironmental regulation of breast
cancer metastasis". (NB: 10:00 hrs).
October 31: Wendy Bickmore "Spatial
Genome organisation and gene regulation".
November 7: Eva van Rooij "MicroRNA
function in cardiac disease".
November 21: Kim Nasmyth "What holds
chromosomes together".
November 28: Jan-Paul Medema "Colon
cancer heterogeneity".
December 5: Maarten van Lohuizen "Role
of Polycomb repressors in stem cells,
cancer and development".
December 12: Carlos Caldas "Breast
cancer: moving on from intrinsic subtypes
to a genome driver-based classification".
January 16: Reinhard Dummer.
January 23: Yitzhak Pilpel.
January 30: Luis Blanco
February 6: Anja Groth "Chromatin
replication and epigenome maintenance".
March 27: Roger Greenberg.
April 17: Nicholas Dyson.
Further info at www.nki.nl
Seminars in the lecture series Frontiers in
Science in the low countries:
Bij de afdeling Pathologie (Leiden):
MGC-Bulletin no. 51; September 2014
Noel de Miranda is gestart als postdoc op
het door de MLDS gesubsidieerde project
"Identifying mutations in novel DNA Repair
genest hat cause familial colorectal
cancer".
6
September 23: Prof.dr. P. van der Spek,
Bioinformatics
October 21: Dr. F. Hoebeek, Neuroscience
November
18:
Dr.
W.
Baarends,
Reproduction and Development
January 20: Dr. J. Marteijn, Genetics
February
17:
Dr.
T.
Mahmoudi,
Biochemistry
March 17: Dr. T. van Ham, Clinical
Genetics
April 21: Dr.ir. N. Galjart, Cell Biology.
These lectures are given at Erasmus MC
on Tuesdays from 16.00 – 17:00 uur, with
drinks afterwards to animate discussions.
Further
info
at
http://intranet.erasmusmc.nl/biomedicalscie
nce/lectures/agenda.
Sectie 'DNA herstel-mechanismen'
De volgende bijeenkomst zal plaatsvinden
op vrijdag 7 november in Leiden, LUMC,
aanvang 9.30 uur. Deze sectie komt ca. 1 x
per
2
maanden
bijeen
op
een
vrijdagochtend, alternerend in Leiden en
Rotterdam. Coördinatoren: Haico van
Attikum (: 071-5269624) en Wim
Vermeulen (: 010-7043194).
Sectie ‘Lysosomal Storage Diseases’
Eens per week overleggen betrokkenen
van de afdelingen Kindergeneeskunde,
Klinische Genetica, Neurologie, Interne
Geneeskunde, Ziekenhuis Apotheek en
andere afdelingen van het Erasmus MC
over de lopende zaken wat betreft
patiëntenzorg en onderzoek aangaande
lysosomale stapelingsziekten. Hierbij staat
de toepassing van enzymvervangingstherapie en daaraan gerelateerd onderzoek
centraal (ziekte van Pompe, ziekte van
Hurler, ziekte van Hunter en MaroteauxLamy).
De bijeenkomsten worden gehouden in het
Sophia kinderziekenhuis, Dr Molewaterplein 60, Rotterdam. Voor meer informatie
kunt U terecht bij Pim Pijnappel: 0107043357; w.pijnappel@erasmusmc.nl.
Verkregen subsidies
Danielle
Majoor-Krakauer
(Klinische
Genetica, EMC) heeft van de Stichting Lijf
en Leden een grant ontvangen voor haar
MGC-Bulletin no. 51; September 2014
7
project "Genes, molecular mechanisms and
risk prediction for abdominal aortic
aneurysm (AAA)". AAA is highly prevalent
in the population above the age of 65
years. Since targeted ultrasound screening
of persons at high risk allows reduction of
AAA related mortality, a risk prediction
model based on clinical characteristics and
biomarkers is needed to identify timely the
persons at risk.
We aim to find molecular markers for AAA
by identifying genes, pathways and cellular
mechanisms involved in remodeling of the
vascular wall of the aorta in AAA. In
collaboration with the departments of
vascular surgery and genetics, a large
study cohort of patients, including >100
families with multiple affected individuals,
was constructed allowing DNA, RNA and
tissue analysis of patients. Which are used
together with mouse and human cellular
models to identify underlying pathways and
molecular mechanisms predisposing to
AAA.
Grazia Mancini (Klinische Genetica, EMC)
heeft een Erasmus Grant ontvangen voor
haar onderzoek "Cilia-related defects in
brain developmental disorders".
Dr. Mandemakers (Klinische Genetica,
EMC) heeft een subsidie ontvangen van
het Erasmus MC voor zijn promotietraject
"Neuronal
differentiation
of
human
fibroblast derived iPSCs as a model system
for Parkinson’s disease".
Jurgen Marteijn (Genetica, EMC) heeft
een VIDI beurs toegekend gekregen. Hij
neemt DNA reparatie onder de loep: "DNA
schade verstoort transcriptie. Hierdoor
kunnen cellen sneller doodgaan, wat kan
leiden tot versnelde veroudering. We
besturende,
met
geavanceerde
microscoop- en eiwitanalyses, in levende
cellen de werking van eiwitten betrokken bij
reparatie van deze DNA schade".
Christine
Mummery
(Anatomie
&
Embryologie, LUMC) heeft samen met Dr.
P. Passier en Dr. S. Braam (Pluriomics) de
Hugo van de Poelgeest prijs ontvangen
voor 'Animal Alternatives' (15k euro).
Louise van der Weerd (Humane
Genetica, LUMC) heeft een NWO VIDI
subsidie gehonoreerd gekregen voor haar
onderzoek. Beschadigde bloedvaten in het
brein
en
eiwitophopingen
in
de
hersenvaten kunnen hersenbloedingen
veroorzaken.
Met
beeldvormende
technieken zoals MRI wordt bekeken hoe
dit proces verloopt en welke bestaande
geneesmiddelen zouden kunnen helpen
om de eiwitophopingen te verminderen of
de bloedvaten sterker te maken.
Personalia/Prijzen
Vincenzo Bonifati (Klinische Genetica,
EMC) heeft op 11 april zijn inaugurele rede
uitgesproken getiteld "Unravelling the
Parkinson's code".
Op vrijdag 16 mei 2014 heeft Leon
Mullenders officieel afscheid genomen als
hoofd van de afdeling Toxicogenetica
(LUMC). Ter ere van zijn afscheid was het
dagsymposium 'DNA damage response
and human disease, Nucleotide Excision
Repair over the ages' georganiseerd in
museum
Naturalis,
waar
bevriende
collega's uit binnen- en buitenland spraken
over hun werk en de samenwerking met
Mullenders.
"Humane Genetica, in het bijzonder de
moleculaire en functionele genetica van
cystenieren".
Marije Meuwissen heeft de Young
Investigator Award van de European
Society of Human Genetics gewonnen.
Wim Vermeulen (Genetica, EMC) is per 1
september door het Trustfonds van de
Erasmus
Universiteit
benoemd
tot
bijzonder
hoogleraar
"Genetische
Stabiliteit".
Silvère van der Maarel heeft op 4
september de Prinses Beatrix Spierfonds
Wetenschapsprijs
uitgereikt
gekregen
tijdens de voorstelling 'Free to move' in het
Lucenta Danstheater te Den Haag.
Van der Maarel heeft de prijs van 1 miljoen
euro gekregen voor zijn baanbrekende
onderzoek naar de erfelijke spierziekte
FSHD, facioscapulohumerale dystrofie.
Foto: Frank van Beek
Overige mededelingen


Rob Willemsen (Klinische Genetica, EMC)
heeft op 23 mei zijn inaugurele rede
uitgesproken getiteld "De verwondering
begrijpen".
Dorien Peters (Humane Genetica, LUMC)
is per 1 juni benoemd tot hoogleraar
MGC-Bulletin no. 51; September 2014
8
Met ingang van 1 juli is de afdeling
Toxicogenetica (LUMC) geïntegreerd
in de afdeling Humane Genetica
(LUMC). Prof. Silvère van der Maarel
is
hoofd
van
deze
grote
onderzoeksafdeling.
Deze zomer is Toxys van start
gegaan. Dit spin-off bedrijf van het
LUMC test nieuwe stoffen op
kankerverwekkende eigenschappen.
“Daarvoor
gebruiken
we
onze
ToxTracker assay, een systeem dat
gebruik maakt van stamcellen”, vertelt
directeur dr. Giel Hendriks (Humane
Genetica, LUMC). Uniek hieraan is dat
het niet alleen laat zien dat een stof
kankerverwekkend is, maar ook hoe
dat komt.
Minder
proefdieren
“Farmaceutische en chemische stoffen
die met deze nieuwe in vitro-techniek
kankerverwekkende
eigenschappen
blijken te hebben hoeven niet meer in
proefdieren getest te worden”, aldus
Hendriks.
De onderzoeker ontving begin dit jaar
een NGI Pre-Seed grant, een subsidie
die onderzoekers de mogelijk geeft om
een bedrijf te kunnen beginnen. Toxys
B.V. maakt op dit moment nog gebruik
van de faciliteiten van het LUMC.
Hendriks werkt voor 20 procent als
onderzoeker bij de afdeling Humane
Genetica, de rest van zijn tijd besteedt
hij aan Toxys.
Mogelijkheden bespreken
Heeft u interesse in Toxys? Bekijk de
website van Toxys (www.toxys.com)
en neem gerust contact op met Giel
Hendriks om de mogelijkheden te
bespreken, zoals wetenschappelijke
samenwerkingen of het gezamenlijk
indienen van een subsidie-aanvraag
(public-private partnership).
MGC-Bulletin no. 52
Het twee-en-vijftigste MGC Bulletin is
gepland
voor
maart
2015.
De
sluitingsdatum voor kopij is gesteld op
15 februari 2015. Mededelingen, nieuws,
agendapunten
en
andere
wetenswaardigheden gaarne per e-mail inleveren
bij Madeleine Nivard of Ingrid Braxhoven, ,
Nivard@lumc.nl/ I.Braxhoven@lumc.nl, afdeling Humane Genetica.
MGC-Bulletin no. 51; September 2014
9
24th MGC-SYMPOSIUM
Friday, September 19, 2014
"Engels", Stationsplein 45, Rotterdam
Program 24th MGC Symposium
8.45
9.30
9.35
9.55
10.15
10.35
Coffee and registration
Opening: Prof.dr. Leon Mullenders
Chairman: Prof.dr. Jan Hoeijmakers
Simone Olgiatio: "An Exome study of Parkinson's disease in Sardinia, a Meditteranean genetic
isolate" (Clinical Genetics, Erasmus MC)
Eleonora de Klerk: "Mapping ribosome footprints to investigate translational control during
myogenesis" (Human Genetics, LUMC)
Parham Solaimani: "An unexpected requirement for Gpr56 revealed by whole transcriptome
analysis of endothelial-to-hematopoietic stem cell transition" (Cell Biology, Erasmus MC)
Best lecture of the MGC PhD Workshop 2014
Risha Smeding: "Genetic paleo-epidemiology: medically relevant polymorphisms in ancient
human populations" (Human Genetics, LUMC)
10.55
11.20
11.40
12.00
12.20
Coffee/tea
Chairman: Prof.dr. Bob van de Water
Kirsten van Dycke: "Circadian disruption and increased breast cancer risk" (Genetics,
Erasmus MC and RIVM)
Bas ter Braak: "Mammary gland tumor promotion by chronic administration of different insulin
analogues in the p53R270H/+WAPCre mouse model" (LACDR, UL)
Kishan Naipal: “Functional ex vivo assay to select homologous recombination deficient breast
tumors for PARP inhibitor treatment” (Genetics, Erasmus MC)
Robin van Schendel: "Polymerase Theta: stitching genomic wounds at a small expense"
(Human Genetics, LUMC)
12.40 -14.00
14.00
14.20
14.40
15.00
15.20
Chairman: Prof.dr. Silvère van der Maarel
Tjakko van Ham: "The role of non-neuronal cellular dynamics in neurodegeneration: learning
from the zebrafish" (Clinical Genetics, Erasmus MC)
Anke Smits: "Optimising the cardiac post-injury response; identifying novel regulators of
epicardial EMT" (Molecular Cell Biology, LUMC)
Sabine den Hartogh: "Unravelling mesoderm to cardiac progenitor differentiation by using a
Mesp1-mCherry-NKX2-5-eGFP dual reporter human embryonic stem cell line (Anatomy and
Embryology, LUMC)
Guillaume Giraud: "Co-recruitment of Fli-1 and the Ldb1 complex to regulatory sequences of
megakaryocytic genes" (Cell Biology, Erasmus MC)
Fabrizio Carofiglio: "Zooming-in on chromosomes in mouse meiosis" (Reproduction and
Development, Erasmus MC)
15.40
16.10
Lunch
Coffee/tea
Chairman: Prof.dr. Frank Grosveld
MGC Symposium Lecture: Prof. dr. James Briscoe: "The Gene Regulatory Logic for Reading
the Sonic Hedgehog Gradient In The Vertebrate Neural Tube" (MRC National Institute for
Medical Research, Developmental Biology, London, UK)
17.10
Drinks and snacks
18.00-23.30
Buffet dinner with musical accompaniment by the Party Band "Go Yellow"
MGC-Bulletin no. 51; September 2014
10
Abstracts 24th MGC Symposium
An Exome study of Parkinson's disease in Sardinia, a Meditteranean genetic isolate
Simone Olgiatio
Clinical Genetics, Erasmus MC
Objectives: We explore the possibility that a considerable
proportion of patients from the genetically isolated population of
Sardinia are explained by rare variants of strong effect.
Background: Parkinson’s disease (PD) is a common
neurodegenerative disorder of complex etiology. Rare, highlypenetrant PD-causing mutations and common risk factors of small
effect-size have been identified in several genes/loci. However,
these mutations and risk factors only explain a fraction of the
disease burden, suggesting that additional, substantial genetic
determinants remain to be found. Genetically isolated populations
offer advantages for dissecting the genetic architecture of complex
disorders, such as PD.
Methods: We performed exome sequencing in 100 unrelated PD
patients from Sardinia, a genetic isolate. SNPs leading to missense, nonsense, splice-site
changes, or located in 5’- or 3’-UTR regions, that were absent in dbSNP129 and
1000Genomes, and shared by at least 5 unrelated patients (n= 3,881 SNPs) were prioritized
and genotyped in 500 independent Sardinian individuals (242 PD and 258 controls). Variants
associated with PD with nominal p-value <0.5, and those with odds-ratio >3 (n=155) were
validated by Sanger sequencing, yielding 26 SNPs, that were then typed in a replication
sample of 2,965 patients and 2,678 controls from Italy, Spain and Portugal.
Results: We identified novel moderately-rare variants in several genes that were specifically
present in PD patients or enriched among them, nominating these as novel candidate risk
genes for PD. Although no variants achieved genome-wide significance after Bonferroni
correction, these findings represent an important resource for follow-up studies.
Conclusions: Our study suggests that the genetic bases of PD are highly heterogeneous,
with implications for designing future large-scale exome or whole-genome analyses of this
disease.
Mapping ribosome footprints to investigate translational control during myogenesis
Eleonora de Klerk
Human Genetics, LUMC
The formation of skeletal muscles is associated with drastic
changes in protein requirements. These changes are safeguarded
by tight control over transcription and mRNA processing. The
importance of regulation of mRNA translational for the correct
orchestration of myogenesis is currently less clear. Regulation at
translational level may affect the abundance and the identity of
proteins. Use of alternative translation initiation sites (TISs) in
upstream open reading frames (uORFs) may increase or decrease
protein synthesis, whereas alternative open reading frames
(aORFs) may produce entirely different proteins.
We applied ribosome profiling to monitor translation during
myogenic differentiation of C2C12 cells. We simplified the existing protocol and developed a
dedicated pipeline to identify TISs and quantify translation activity. We identified 5333
unannotated TISs, providing a catalogue of alternative TISs leading to uORFs and aORFs.
By comparing ribosome profiling and DeepCAGE data, we found 312 genes that switched to
an alternative TIS, which could not be explained by alternative promoter usage. Many of
MGC-Bulletin no. 51; September 2014
11
these genes were ribosomal protein genes and genes involved in calcium signaling. The
same pathways demonstrated discrepant total RNA and ribosome-associated RNA level. Our
data therefore suggest that ribosome biogenesis and calcium signaling are most strongly
regulated at the translational level, while the majority of differences in protein requirements
during myogenesis are ensured by changes at transcriptional level.
An unexpected requirement for Gpr56 revealed by whole transcriptome analysis of
endothelial-to-hematopoietic stem cell transition
Parham Solaimani
Cell Biology, Erasmus MC
Hematopoietic stem cells (HSCs) are generated via a natural
transdifferentiation process known as endothelial-to-hematopoietic cell
transition (EHT). Due to small numbers of embryonal arterial cells
undergoing EHT and the paucity of markers to enrich for hemogenic
endothelial cells, the genetic program driving HSC emergence is largely
unknown. Here, we use a highly sensitive RNAseq method to examine
the whole transcriptome of small numbers of enriched aortic HSCs,
hemogenic endothelial cells and endothelial cells. Gpr56, a G-protein
coupled receptor, is one of the most highly upregulated of the 530
differentially expressed genes. Also, highly upregulated are
hematopoietic transcription factors, including the ‘heptad’ complex of factors. We show that
Gpr56 (mouse and human) is a target of the heptad complex and is required for
hematopoietic cluster formation during EHT. Our results identify the processes and
regulators involved in EHT and reveal the surprising requirement for Gpr56 in generating the
first HSCs.
Best lecture of the MGC PhD Workshop 2014
Genetic paleo-epidemiology: medically relevant polymorphisms in ancient human
populations
Risha Smeding
Human Genetics, LUMC
Many common deleterious or advantageous phenotypes
are known to be caused by or associated with certain
genetic variants. Surprisingly enough, we see relatively high
frequencies of some deleterious genetic variants in modern
populations, associated with diseases like Type II Diabetes
or Haemochromatosis. Why is that so? Maybe we are
genetically better adapted to different, perhaps more
adverse, environmental conditions; conditions like those of
our medieval ancestors. Were certain (risk)alleles already
present in ancient populations? And if so, at what frequency? Did these frequencies change
over time, following the severe environmental changes of recent times? If we want to answer
these questions we need to look at the genomes of our ancestors.
We have successfully extracted DNA from medieval and post-medieval skeletons from
different locations throughout the Netherlands. In order to check for the presence of certain
genetic variants in the past, a multiplex SNP-kit was designed typing 23 medically relevant
polymorphisms existing of 21 SNPs and 2 indels. Among the targeted polymorphisms are
variants associated with or causative for Lactose Tolerance, HIV-resistance, Type II
Diabetes, Obesity, Pro-inflammatory response, Coeliac Disease, Cystic Fibrosis,
Osteoarthritis, Longevity and Haemochromatosis. Following PCR the short fragments of
between 45 and 79bp were sequenced on the Ion PGM Torrent. In order to explore the
changes of allele frequencies through time, skeletal remains from different time periods were
MGC-Bulletin no. 51; September 2014
12
typed (1000-1850 AD). Furthermore a number of modern blood donors from the same region
as the medieval skeletons were included for comparison with modern population.
In this pilot study we successfully typed medically relevant polymorphisms in 100 (post-)
medieval skeletons from two different sites in the Netherlands: Vlaardingen and Eindhoven.
The preliminary results show that for a small number of the typed polymorphisms we seem to
detect a significant pairwise difference in allele frequency between the ancient and modern
populations. Further research, including simulation studies, is required to see if these
differences in frequency can be the result of selection.
Circadian disruption and increased breast cancer risk
Kirsten van Dycke
Genetics, Erasmus MC and RIVM
Recent epidemiological studies suggested an association between
frequent night shift work and increased breast cancer risk. Possible
mechanisms or causal factors are however lacking. Animal studies can
provide insight into the causality between circadian rhythm disruption and
cancer risk.
In contrast to previous studies, which mostly used chemically-induced
breast tumors or xenografts, we use the humanized Li-Fraumeni
p53R270H/+ WAPCre mouse model. Female p53R270H/+ WAPCre mice
spontaneously develop mammary gland tumors (thus mimicking human
cancer development), which allows us to study the relationship between
circadian rhythm disruption (CRD) and increased breast cancer risk unequivocally. Mice
were subjected to chronic circadian disruption (CRD) by exposing them lifelong to weekly
alternating light-dark cycles. Li-Fraumeni female mice housed under control normal light dark
conditions displayed a tumor latency time of 50.3 weeks, whereas CRD exposed animals
(n=25) showed a markedly shortened tumor latency time of 42.6 weeks. In addition, CRD
exposed animals showed an increase in body weight compared to the unexposed controls.
Bodyweight gain could be explained neither by changes in feed intake nor by alterations in
locomotor activity.
Within this study, we are the first to provide unequivocal evidence that CRD is a risk factor
for breast cancer development. Shift work will remain part of our society and due to the
growing 24-hr economy will even increase. Therefore, it is important to understand the
molecular mechanisms underlying the chronic adverse health effects induced by CRD, which
allows us to develop interventions that at least suppress, and ultimately may prevent the
adverse health effects arising from chronic CRD. Currently, we are identifying biomarkers for
CRD, which might be helpful in designing intervention strategies. The final goal will be to
validate the identified biomarkers in large-scale human cohort studies.
MGC-Bulletin no. 51; September 2014
13
Mammary gland tumor promotion by chronic administration of different insulin
analogues in the p53R270H/+WAPCre mouse model
Bas ter Braak
LACDR-Toxicology, UL
Diabetes is an ever increasing disease which can be treated with
insulin analogues, which are chemically modified insulin
molecules with improved pharmacokinetic parameters compared
to regular human insulin. Insulin analogues may bind both insulin
receptors (INSR) as well as the more mitogenic insulin-like
growth factor receptors (IGFR). Although these compounds have
been tested for carcinogenic side-effects with the standard twoyear in vivo assays in rodents, there are some concerns raised
by several epidemiological studies in which an association is
suggested between the use of some insulin analogues and the
cancer incidence in these diabetic patients.
In this study the p53R270H/+WAPCre mouse model was used. These mice have a specific point
mutation in the tumor suppressor p53 gene, which corresponds with a hotspot mutation in
human tumors. WAPCre ensures selective expression of mutated p53 in the mammary gland
and as a result all female mice will develop spontaneous mammary gland tumors. We
performed life-long injections of the mice with different insulin analogues: insulin NPH, insulin
glargine, insulin X10 (AspB10) or IGF1. We hypothesized that injections with possible
carcinogenic insulin compounds would increase the number of tumors that are formed,
decrease the latency time for tumor development, or lead to different types or more
aggressive tumors. We found that both X10 and IGF1, which both act on the IGFR,
significantly decreased the latency time for tumor development (for glargine a slight, nonsignificant effect was observed). A Western blot analysis was done on all primary mammary
gland tumors (n=170) to investigate the IR/IGF1R/HER2/ESR/p-Ekt/-p-Akt/ and cadherin
status. Hierarchical clustering of this data revealed that X10 and IGF1 induced tumors
showed a distinct protein-expression profile that was characterized by high p-Erk levels,
suggesting an important role of MAPK signalling cascade in tumor progression/initiation in
insulin analogue induced tumors. We further characterized a large subset of these tumors
using RNA-sequencing. Gene-expression and mutational profiling will shed light on tumor
progression processes and possibly tumor initation.
These results indicate a hazard for insulin-analogues with intrinsic mitogenic capacity for the
promotion of mammary tumor development. Further evaluation of this hazard in other cancer
models as well as understanding the mechanism of this enhanced tumor development will be
important for future studies.
Functional ex vivo assay to select homologous recombination deficient breast tumors
for PARP inhibitor treatment
Kishan Naipal
Genetics, Erasmus MC
Purpose: Poly(ADP-Ribose) Polymerase (PARP) inhibitors are
promising targeted treatment options for hereditary breast tumors
with a Homologous Recombination (HR) deficiency caused by
BRCA1 or BRCA2 mutations. However, the functional consequence
of BRCA gene mutations is not always known and tumors can be HR
deficient for other reasons than BRCA gene mutations. Therefore, we
aimed to develop a functional test to determine HR activity in tumor
samples to facilitate selection of patients eligible for PARP inhibitor
treatment.
Experimental design: We obtained 54 fresh primary breast tumor
MGC-Bulletin no. 51; September 2014
14
samples from patients undergoing surgery. We determined their HR capacity by studying the
formation of ionizing radiation induced foci (IRIF) of the HR protein RAD51 after ex vivo
irradiation of these organotypic breast tumor samples. Tumors showing impaired RAD51
IRIF formation were subjected to genetic and epigenetic analysis.
Results: Five out of 45 primary breast tumors with sufficient numbers of proliferating tumor
cells were RAD51 IRIF formation deficient (11%, 95%CI: 5%-24%). This HR defect was
significantly associated with Triple Negative Breast Cancer (OR:57, 95%CI: 3.9-825,
p=0.003). Two out of five HR deficient tumors were not caused by mutations in the BRCA
genes, but by BRCA1 promoter hypermethylation.
Conclusion: The functional RAD51 IRIF assay faithfully identifies HR deficient tumors and
has clear advantages over gene sequencing. It is a relatively easy assay that can be
performed on biopsy material, making it a powerful tool to select patients with an HRdeficient
cancer
for
PARP
inhibitor
treatment
in
the
clinic.
Polymerase Theta: stitching genomic wounds at a small expense
Robin van Schendel
Human Genetics, LUMC
DNA lesions that block replication fork progression are drivers of
cancer-associated genome alterations, but the error-prone DNA
repair mechanisms acting on collapsed replication are incompletely
understood, and their contribution to genome evolution largely
unexplored. By whole genome sequencing of animal populations
that were clonally propagated for over 50 generations, we identify a
distinct class of deletions from 50-300 basepairs that spontaneously
accumulate in C. elegans strains lacking translesion synthesis (TLS)
polymerases. Emerging DNA double-strand breaks are repaired via
an error-prone mechanism in which the outermost nucleotide of one
end serves to prime DNA synthesis on the other end. This pathway
critically depends on the A-family polymerase theta (θ), which
protects the genome against gross chromosomal rearrangements. By comparing the
genomes of isolates of C. elegans from different geographical regions, we found that in fact
most spontaneously evolving structural variations match the signature of polymerase thetamediated end joining (TMEJ), arguing that TMEJ is an important source of genetic
diversification.
The role of non-neuronal cellular dynamics in neurodegeneration: learning from the
zebrafish
Tjakko van Ham
Clinical Genetics, Erasmus MC
Many incurable brain diseases, including Alzheimer’s disease, involve
activity of the immune system. Although immune responses represent
a potential target to treat disease, it is unknown whether and when
immune cells are harmful or act protectively. We want to uncover how
immune cells, including microglia, the brain’s resident macrophages,
respond to cues related to brain disease, and how their activity
contributes to recovery or deterioration of brain tissue. Furthermore, to
better understand these responses we aim to identify signalling
pathways controlling their activity.
To study these questions we use the zebrafish. The zebrafish genome,
brain and immune system are highly conserved with mammals. Zebrafish larvae are
transparent and immune cells can be tracked in vivo with great detail using intravital
MGC-Bulletin no. 51; September 2014
15
microscopy [1,2]. To elucidate the spatiotemporal immunological events upon neuronal cell
death genetically-targeted cell ablation specifically inducing cell death in the nervous system
is used, followed by tracking of immune cells by high resolution intravital imaging. Initial
clearance of dead neurons occurs by increased numbers of infiltrating macrophages and
resident microglia [2,3]. Following clearance of dead neurons, their numbers in the brain
decrease by migration, apoptosis and engulfment by microglia, revealing the chronological
cellular sequence of resolution of neuroinflammation. Our most surprising finding is that
immune cells in the brain undergo apoptosis and are engulfed by microglia. This concept has
not previously been described in the brain, and suggests that inflammation in the brain can
be resolved in a way similar to a peripheral wounding response, but involving different cell
types. Our current studies focus on identifying pathways controlling these immune responses
in the brain to help understand and ultimately benefit treatment of human brain diseases.
Optimising the cardiac post-injury response; identifying novel regulators of epicardial
EMT
Anke Smits
Molecular Cell Biology, LUMC
Cell-based therapy has been proposed to treat patients after myocardial
infarction (MI) in an attempt to replace lost contractile tissue. Cell
transplantation studies using progenitor cells with the potential to
differentiate into new cardiac tissue have shown to be safe and feasible
but the retention of cells is low and the effect on cardiac performance is
limited. Therefore the local activation of progenitor cells in the heart
itself may be more promising.
During development, the epicardium (the outer layer of the heart) is
formed from the pro-epicardial organ. Epicardial cells undergo epithelial
to mesenchymal transition (EMT) and migrate into the developing
myocardium where they differentiate into several cardiac cell types. In the adult heart, the
epicardium is quiescent but upon damage it becomes reactivated again resulting in EMT and
migration. Epicardial derived cells have been shown to differentiate into cardiomyocytes,
showing the potential of these cells as progenitor cells and their ability to participate in
cardiac regeneration. In this project we aim to identify novel regulators of epicardial EMT in
an attempt to increase the number of epicardial cells participating in the post-injury
response.
Unravelling mesoderm to cardiac progenitor differentiation by using a Mesp1mCherry-NKX2-5-eGFP dual reporter human embryonic stem cell line
Sabine den Hartogh
Anatomy and Embryology, LUMC
Human pluripotent stem cells (hPSCs) have the potential to
differentiate into any cell type of the human body. This makes
the use of hPSCs of interest for regenerative medicine, drug
screenings and embryonic development. Several optimized
differentiation protocols of hPSCs to cardiomyocytes have been
generated, including growth factor directed differentiations as
monolayers or as three-dimensional aggregates. Different
studies have demonstrated that hPSC-derived cardiomyocytes
(hPSC-CMs) faithfully recapitulate the early molecular events
during embryonic development. Recently, we have generated a
cardiac reporter line in human embryonic stem cells (hESC) by introducing Green
Fluorescent Protein (GFP), in the genomic locus of the early cardiac transcription factor
MGC-Bulletin no. 51; September 2014
16
NKX2-5, which enables us to visualize the derivation of NKX2-5+ cardiomyocytes during in
vitro differentiation and purify these cells by Fluorescent Activated Cell Sorting (FACS).
Transcription factor Mesp1 is a key regulator of pre-cardiac mesoderm and represents the
earliest marker of cardiovascular progenitors. In order to identify early cardiac progenitors
and the molecular mechanisms involving their further cardiovascular differentiation in vitro,
we generated a MESP1-mCherry-NKX2-5-eGFP hESC -dual reporter line. Cardiac
differentiation of MESP1-mCherry-NKX2-5-eGFP hESCs resulted in the transient activation
of mCherry expression with a peak at day 3-4, recapitulating mesodermal differentiation. We
further show the characteristics of these Mesp1-mCherry expressing cells, and their ability to
efficiently differentiate towards the cardiac lineage in the presence of Wnt-pathway inhibitor
Xav939. This model allows us to unravel mechanisms that are important for expansion of
cardiac mesoderm and the transition to cardiac progenitors and their derivatives. A better
understanding of these processes will be beneficial for optimization of differentiation
protocols towards specific subtypes of cardiac cells, which will be of high interest for clinical
and/or pharmaceutical applications.
Co-recruitment of Fli-1 and the Ldb1 complex to regulatory sequences of
megakaryocytic genes
Guillaume Giraud
Cell Biology, Erasmus MC
Hematopoiesis is the hierarchical process by which hematopoietic stem
cells (HSC) give rise to all mature blood cells through multipotent and
oligopotent progenitors. Every differentiation stages are controlled by
several signals including transcription factors (TF). These signals end with
the activation and the repression of lineage-specific gene expression. We
are particularly interested in the transcriptional control of erythropoiesis
and megakaryopoiesis. Several TF are involved in the development of
both lineages, including Fli-1. This Ets TF is an important protein for the
development of megakaryocytes while it represses erythropoiesis.
Importantly, its high expression in erythroid progenitors is a recurrent
event observed in murine erythroleukemia. However, how Fli-1 works to control these
lineages is not clearly understood. By using an NLS-tagged Fli-1 protein in MEL cells (Murine
ErythroLeukemia) (where a biotag and a 3xFlag sequences have been integrated close to its
NLS (Giraud, NAR, 2014)), we identified several proteins that belong to the Ldb1 complex,
an important TF complex involved in both erythropoiesis and megakaryopoiesis. ChIP-Seq
data for these proteins revealed the co-recruitment of Fli-1 and the Ldb1 complex to
regulatory sequences of megakaryocytic genes whose expression is decreased after Fli-1
repression. Altogether, these data suggest that Fli-1 and the Ldb1 complex cooperate to
activate megakaryocyte genes expression and hence, megakaryopoiesis.
Zooming-in on chromosomes in mouse meiosis
Fabrizia Carofiglio
Reproduction and Development, Erasmus MC
Generation of haploid gametes for sexual reproduction occurs via a
process named meiosis which consists of a single DNA replication
event followed by two subsequent cell divisions (meiosis I and II).
During meiotic prophase I, the replicated genome undergoes
homologous recombination (HR) which serves the dual aim of
mediating genetic shuffling, to generate a unique genetic set to
transfer to the progeny, and of favouring interactions between
MGC-Bulletin no. 51; September 2014
17
homologous chromosomes. Homologous chromosome pairing and synapsis are in fact
essential events to achieve proper meiotic division. In male meiosis, sex chromosomes do
not achieve full synapsis due to their extensive heterology. This triggers a silencing
mechanism (MSCI) that compartmentalizes the X and Y chromatin, rendering it
transcriptionally inactive. Homologous recombination in meiotic cells is triggered by the
induction of DNA double-strand breaks (DSBs) by the meiosis-specific transesterase SPO11.
Repair of such DSBs via HR requires an intact template for repair which, in meiocytes, can
be either the sister chromatid or the homologous chromosome. In order to favour interactions
between homologs, DSB repair via the sister chromatid is repressed. As a consequence, the
unsynapsed X chromosome shows persistent DSBs even after the autosomes have
completed repair of the meiotic DSBs. When SPO11 is not functional and meiotic DSBs are
not induced, HR does not take place and homologous chromosome pairing and synapsis are
impaired. Despite extensive asynapsis, a silenced chromatin area is still observed which
does not always coincide with the X and Y chromosomes. Using a SPO11-inactive mouse
model we investigated the role of SPO11 protein and activity in the meiosis-specific events of
chromatin silencing, homologous chromosome pairing and synapsis. We also applied state
of the art microscopy techniques to study the sites of meiotic DSBs in the context of
chromosome organization and DNA repair protein recruitment to the chromosomes.
MGC Symposium Lecture
The Gene Regulatory Logic for Reading the Sonic Hedgehog Gradient In The
Vertebrate Neural Tube
Prof. dr. James Briscoe
MRC National Institute for Medical Research, Developmental Biology, London, UK
The generation of the correct neuronal subtype at the
appropriate position and time in the vertebrate neural tube is
the first step in the assembly of functional neural circuits. It
also represents one of the best-studied examples of
embryonic pattern formation. Distinct neuronal subtypes are
generated in a precise spatial order from progenitor cells
according to their location along the anterior-posterior and
dorsal-ventral axes. Underpinning this organization is a
complex network of extrinsic and intrinsic factors.
Particularly well understood is the mechanism that
determines the generation of different neuronal subtypes in
ventral regions of the spinal cord. In this region of the
nervous system, the secreted protein Sonic Hedgehog
(Shh) acts in graded fashion to organize the pattern of neurogenesis. This is a dynamic
process in which increasing concentrations and durations of exposure to Shh generate
neurons with successively more ventral identities. Interactions between the receiving cells
and the graded signal underpin the mechanism of Shh action. In particular, the regulation of
transcription factors induced or repressed by Shh signaling play an essential role in
determining the graded response of cells. Thus the accurate patterning of the neural tube
and the specification of motor neurons and the other neuronal subtypes characteristic of this
region relies on the continuous processing and constant refinement of the cellular response
to graded Shh signaling.
MGC-Bulletin no. 51; September 2014
18
De MGC bestuurders en hun instituten
Instituut Celbiologie
 010-7043593
Erasmus MC
Postbus 2040, 3000 CA Rotterdam
hoofd: Prof.dr. D.F.E. Huylebroeck
(lid MGC bestuur)
Centrum voor Humane en Klinische
Genetica, LUMC
 071-5269400
Postbus 9600, 2300 RC Leiden
hoofd: Prof.dr. S.M. van der Maarel
(lid MGC bestuur)
Instituut Genetica
 010-7043199
Erasmus MC
Postbus 2040, 3000 CA Rotterdam
hoofd: Prof.dr. J.H.J. Hoeijmakers
(lid MGC bestuur)
Afdeling Humane Genetica
 071-5269600
Leids Universitair Medisch Centrum
Postbus 9600, 2300 RC Leiden
Prof.dr. L.H.F. Mullenders
(voorzitter MGC bestuur)
LACDR/ Toxicology  071-5276223
Faculteit W&N, Universiteit Leiden
Postbus 9502, 2300 RA Leiden
hoofd: Prof.dr. B. van de Water
(lid MGC bestuur)
Instituut Klinische Genetica  010-7043198
Erasmus MC
Postbus 2040, 3000 CA Rotterdam
hoofd: Prof.dr. R.M.W. Hofstra
(secretaris MGC bestuur)
Andere instituten/groepen binnen het MGC
Moleculaire Celbiologie, LUMC: (Prof.dr. H.J. Tanke & Prof.dr. A.K. Raap, Prof.dr. J. Noordermeer &
Dr. L. Fradkin, Prof.dr. R. Hoeben, Prof.dr. J.A. Maassen en Prof.dr. P. ten Dijke)
Neurologie, groep neurogenetica, LUMC (Prof.dr. R.A.C. Roos, Prof.dr. J.J.G.M. Verschuuren
en Prof.dr. M.D. Ferrari)
Huid- en geslachtsziekten, groep erfelijke melanomen, LUMC (Prof.dr. R. Willemze, Prof.dr. W.
Bergman, Dr. F. de Gruijl en Dr. N.A. Gruis)
Pathologie: moleculaire tumorpathologie, LUMC (Prof.dr. P.C.W. Hogendoorn, Prof.dr. J. Morreau,
Prof. J.V.M.G. Bovee en Prof.dr. P. Devilee)
Medische Statistiek: Moleculaire epidemiologie, LUMC (Prof.dr. P.E. Slagboom)
Anatomie en Embryologie, LUMC (Prof.dr. C.L. Mummery)
Optical Imaging Centre (OIC), Department of Pathology, Erasmus MC (Prof. Dr. A. B. Houtsmuller)
Kinderheelkunde, Ontwikkelingsbiologie groep, Erasmus MC (Prof.dr. D. Tibboel)
Genetische epidemiologie, Erasmus MC (Prof.dr. C.M. van Duijn)
Afd. Voortplanting en Ontwikkeling, Erasmus MC (Prof.dr. J.A. Grootegoed)
Forensische Moleculaire Biologie, Erasmus MC (Prof.dr. M. Kayser)
Bioinformatica, Erasmus MC (Prof.dr. P. van der Spek)
Biochemie, Erasmus MC (Prof.dr. P. Verrijzer)
[n.b. verbeteringen voor deze lijst gaarne doorgeven aan het secretariaat]
Het MGC secretariaat
is gevestigd op de afdeling Humane Genetica, Leiden.  071-5269600; Fax 071-5268284
Directie secretaris: Dr. M.J.M. Nivard  071-5269605 e-mail: Nivard@lumc.nl
MGC-Bulletin no. 51; September 2014
19