Transposon and Epigenetic
Regulation
Liang Wu, Haiyun Zhang, Weizhen Cai
Transposon/ Transposable Elements
• All mobile DNA segments in the genome,
regardless of their mechanism of transposition.
• Consists of ~50% of human genome.
• Transpose is the movement of a genetic
element from one location of the genome to
another.
• Retrotransposon and DNA transposons,
autonomous and non-autonomous.
Retrotransposons
R. Keith Slotkin & Robert Martienssen. Nature Reviews Genetics 8, 272-285 (April
2007)
• Derived from viral genome.
• LTR: Long Terminal Repeats.
• Needs to be reverse transcribed.
• SINE (Short Interspersed Elements) and LINE (Long Interspersed
Elements) are non-LTR retrotransposons.
DNA Transposons
Transposase is responsible for
transposition.
Transposase mutated
Miniature Inverted-Repeat
Elements
New member of transposon
R. Keith Slotkin & Robert Martienssen. Nature Reviews Genetics 8, 272-285 (April
2007)
Transposition
Henry L. Levin & John V. Moran. Nature Reviews Genetics 12, 615-627 (September 2011)
Consequences
Richard Cordaux & Mark A. Batzer. Nature Reviews Genetics 10, 691-703 (October 2009)
Transposons are highly mutagenic, cause insertion, chromosome breakage,
recombination and genome rearrangement.
Transposon Needs Regulation
• Number of transposable elements negatively
correlated with fitness of the host.
• Silenced by different mechanisms.
Silencing Mechanisms that Suppress
TEs
•Post-transcriptional silencing of TEs by RNAi
•Chromatin modification
•RNAi-mediated chromatin modification
Post-transcriptional Silencing of
TEs by RNAi
•RNAi
dsRNA
cleaved by Dicer
siRNAs
RISC, Argonaute
Post-transcriptional Silencing of TEs by RNAi
RNAi is the main mechanism of TE silencing
C. elegans, silencing Tc1 DNA transponson in germ line
Mutations in both argonaute- and dicer- family
proteins cause the reactivation of TEs in eukaryotic
species
TEs give rise to numerous siRNAs.
How TEs are specifically targeted by RNAi?
stuctures help to distinguish transcripts
Chromatin Modification
• Modification of histone tails
Alert protein factors binding, send information to transcription factors
Methylation of histone H3K9 is a signal for transcriptionally repressive and
inactive chromatin.
• DNA methylation
Cytosine residue, in a symmetrical context (CpG)
Inheritable (mice, DNMT1 DNA methyltransferase)
• Alterations in chromatin packing and condensation
SWI/SNF chromatin-remodelling proteins are required for TE silencing. (plant)
DDM1 in A. thaliana
RNAi-mediated Chromatin Modification
The maintenance of TE silencing at chromatin
level involves both RNAi-independent and RNAi
dependent pathway.
In S. pombe (fission yeast)
RNAi complex works on nascent RNAs
Argonaute proteins (Ago1) cleave nascent RNAs;
the cleavage recruites the histone H3K9
methyltransferase Clr4 to the chromosome,
mechanism unknown.
RNAi is specifically required for spreading H3K9
methylation from repeats into reporter genes.
RNAi-mediated Chromatin Modification
How do TEs that are silenced at the chromatin level produce transcripts
that are to be cleaved into siRNAs?
In A. thaliana, plant-specific RNA polymerase Ⅳ
Loss of PolⅣ can transcriptionally reactive silenced TEs.
PolⅣa: generate siRNAs
PolⅣb: transfer siRNA signal
Symmetrical DNA methylation is heritable; Asymetrical methylation must
be replaced at each cell division (less important).
Targetting mechanism perhaps involves RNAi.
TEs influence the Genomes
•TEs contribute to chromosome form and
function
•TE-induced epigenetic regulation of specific
genes
•Evolutionary implications
TEs contribute to chromosome form and
function
• Centromeres, telomeres and knobs
• PEV and chromatin insulators
• X inactivation
Centromeres and Telomeres
• The centromeres are function as trafficking chromosomes at cell
division. The DNA composition of centromeres differs widely in both
length and primary nucleotide sequence between species, and it is
the specific epigenetic context that confers their function. Thus the
presence of TEs, and the epigenetic silencing apparatus that they
recruit play a role in centromere function.
• The telomeres work for preventing chromosome shortening
following replication. Although whether TEs contribute to telomerelength regulation in mammals remains unknown, recent studies show
that the epigenetic status (predominantly DNA methylation) of
telomeric and sub-telomeric repeats has a role in regulating telomere
elongation in mammalian cells.
KNOB
• A chromosomal knob is a fragment of constitutive heterochromatin
that has no known function.
• Analysis of an A. thaliana knob, composed almost, entirely of fulllength and fragmented TEs (many of which are inserted into each
other), showed that heterochromatin was dependent on the
epigenetic mechanisms of TE silencing.
Position Effect Variegation
(PEV) and chromatin
insulators
• PEV: Heterochromatin can insert into adjacent genes and causes
gene-silencing phenotype. TEs are nucleation centers for the
formation of the type of facultative heterochromatin.
• TEs themselves can function as insulators.
X inactivation
• Female mammals must compensate for their double dosage of Xchromosome genes compared with XY males. This compensation is
achieved by the inactivation and heterochromatinization of one of
the two X chromosomes.
• Inactivation is initiated at the X-chromosome inactivation center
(XIC), and then spreads outwards from the XIC to the rest of the
chromosome.
• TEs function in both the initiation and spread of X inactivation. This is
indirectly supported by a study on mice cells.
TE-induced epigenetic
regulation of specific genes
• Epiallele production and phenotypic variation
• Paramutation
• Imprinting
• V(D)J Recombination
Epiallele production and phenotypic variation
• TE promoters can influence the transcriptio of
nearby genes.
In mice, the intracisternal A-particle (IAP) retrotransposon produces an outward-reading transcript that extends into
the agouti coat-color gene. The level of agouti transcript, and the color of the coat, is subject to the epigenetic status
of the retrotransposon and inheritable.
Paramutation
• Paramutation is an interaction between alleles that results in a
heritable expression change of one allele.
In maize, several genes in the anthocyanin pigmentation
pathway
have paramutable alleles, which are associated with and
pendent
on TEs.
Imprinting
• On the mammalian X chromosome, TEs are
specifically associated with monoallelic
expressed genes that are located on autosomes,
raising the possibility that TEs are involved in the
regulation of imprinted genes.
• The effect of TE-mediated imprinting in
mammals
might be mediated through the action of
DNMT3L
Evolutionary implications
• In the same specie, TEs have the ability to mutate
genes, alter gene regulation and generate new
genes, each providing fuel for evolution.
the stress-induced reactivation of TEs and the
invasion of a new genome by TEs.
• In different species, TEs can generate intraspecies
variation. This happens in virus, plants, and
animals.
Conclusions
• TEs are all mobile DNA segments in the genome. Classified
as retrotransposon, DNA transposon, autonomous and
non-autonomous.
• TEs silencing mechanisms: Post-transcriptional silencing
by RNAi, chromatin modification(H3K9, CpG, SWI/SNF),
RNAi-mediated chromatin modification.
• TEs are involved in many epigenetic mechanisms, from
chromosome form and function to specific genes, playing
significant role in evolutionary history.