Genomics 2015/16
Silvia del Burgo
+ Same genome for all cells that arise from single fertilized
egg, Identity?  Epigenomic signatures
+ Epigenomics: study of chemical changes in DNA and
histones (without altering DNA sequence) that are
inheritable and involved in regulating gene expression,
development, tissue differentiation and suppression of TE.
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–
–
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DNA/histone Methylation
Histone Acetylation
ncRNA
Interactions between distant sections of chromatin
+ Epigenome is dynamic can be altered by environmental
conditions
+ Modification in DNA/histones 
changes in chromatin structure and
function: how easily DNA can be
accessed by TF
+ Promoters & Insulators: chromatin state regarding
histone modification is invariant across cell types.
+ Enhancers: most variable class of
elements between cell types.
+ Other cis-regulatory DNA
sequences.
– Distal to promoters
– Strong evolutionary
conservation
– Marked by hystone
acetylation binding of
coactivator proteins or
DNaseI hypersensitivity
+ 5 important epigenetic marks:
– H3K4me3: promote regions
– H3K4me1: enhancer regions
– H3K36me3: transcribed regions
– H3K27me3: Polycomb repression
– H3K9me3: heterochromatin regions
+ Additional epigenomic marks:
– Acetylation marks H3K27ac and H3K9ac:
increased activation of enhancer and
promotes regions.
– DNase hypersensitivity: accessible
chromatin regions (associated with
regulator binding)
– DNA methylation: associated with
repressed regulatory regions or active gene
transcripts
+ Active states
– Active TSS proximal promotes states
(TssA, TssAFlnk)
– Transcribed state at the 5' and 3' end
of genes showing both promote and
enhancer signatures (TxFlnk)
– Actively transcribed states (Tx, TxWk)
– Enhancer states (Enh, EnhG)
– State associated with Zn finger
protein genes (ZNF/Rpts).
+ Inactive states
– Constitutive heterochromatin (Het)
– Bivalent regulatory states (TssBiv,
BicFlnk, EnhBiv)
– Represses Polycomb states (ReprPC,
ReprPCWk)
– Quiescent state (Quies)
+
+
Inactive states: 68%
Enhancer and promotes states: 5% and
show enrichment for evolutionarily
conserved non-exonic regions.
– Enhancer states contain strong
H3K27ac signal (EnhA1, EnhA2)
show:
 Higher DNA accessibility
 Lower methylation
 High transcription factor
binding
+ Promoter states: low DNA
methylation and high accessibility.
+ Transcribed states: High DNA
methylation and low accessibility
+ Enhancer states: intermediate DNA
methylation and accessibility
– >18.000
– 57% CpG methylation on average
– Strongly enriched in genes
+ DNA methylation patterns are better correlated with
histone methylation patterns than with the DNA sequence/
CpG density
+ CpGs are not distributed uniformly in the genome
– High CpG density sites  unmethylated (hypermethylation
leads to heterochromatin and gene silencing)
– Low CpG density sites  methylated (dynamic)
+ Distribution of methylation levels for CpG in
chromatin states across tissue and cell type:
– TssFlnk (Transcribed state):


Unmethylated in differentiated cells and tissues
Methylated for pluripotent and embryonic-stemcell-derived cells
– Enh and EnhG states (Enhancer states):


Highly methylated in pluripotent cells
Intermediate methylation in differentiated cells
and tissues
– EnhBiv states (Bivalent regulatory states):


Unmethylated in most primary cells and tissues
Broader distribution of methylation levels in
pluripotent cells.
– Repressed states ReprPC: varying
methylation levels among epigenomes
– Het states: high levels of methylation in
almost all epigenomes
Common developmental origin
is a primary determinant of
global DNA methylation
patterns rather than the tissue
environment
+ Primary DNA
sequence has an
impact on the
epigenomic 
histone
modifications and
DNA methylation
can be predicted by
DNA sequence
+ Epigenetic:
– Complex network:
different elements
and relationships
between them
– Epigenetic
signatures should be
studied in the
context of
integrated
chromatin states, in
relation with all
DNA/histone
methylation/acetyla
tion, DNA
accessibility and
RNA transcription.
+ Heintzman ND, Hon GC, Hawkins RD, et al (2009) Histone
modifications at human enhancers reflect global cell-typespecific gene expression. Nature 459:108–112. doi:
10.1038/nature07829
+ Meissner A, Mikkelsen TS, Gu H, et al (2008) Genome-scale
DNA methylation maps of pluripotent and differentiated
cells. Nature 454:766–770. doi: 10.1038/nature07107
+ Roadmap Epigenomics Consortium, Kundaje A, Meuleman
W, et al (2015) Integrative analysis of 111 reference human
epigenomes. Nature 518:317–330. doi:
10.1038/nature14248
+ Romanoski CE, Glass CK, Stunnenberg HG, et al (2015)
Epigenomics: Roadmap for regulation. Nature 518:314–
316. doi: 10.1038/518314a