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Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2
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Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2
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Journal Article
Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2
2012
Overview
Parp1 and Tet2 mediate essential epigenetic remodelling events in an early phase of induced pluripotent stem cell reprogramming, thus directing subsequent induction of the pluripotency loci.
First steps in iPS cell formation
The early epigenetic mechanism by which somatic cells are reprogrammed to induced puripotent stem (iPS) cells by the 'Yamanaka factors' is unknown. Asa Abeliovich and colleagues show that by the fourth day of cellular reprogramming two DNA-modification enzymes, Parp1 and Tet2, are recruited to the endogenous pluripotent loci, such as
Nanog
and
Esrrb
, leading to localized accumulation of modified cytosine bases, 5mC and 5hmC. Parp1 and Tet2 act through separate but overlapping mechanisms to regulate the 5hmC/5mC ratio, which correlates with transcriptional activity. These findings suggest additional roles for 5hmC during epigenetic reprogramming.
Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM)
1
. iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs)
2
. Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as
Nanog
and
Esrrb
. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the
Nanog
and
Esrrb
loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs
3
,
4
). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts
5
,
6
,
7
, our data, and also studies of Tet2-mutant human tumour cells
8
, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Animals
/ DNA
/ DNA-Binding Proteins - metabolism
/ Genetics
/ Homeodomain Proteins - genetics
/ Homeodomain Proteins - metabolism
/ Humanities and Social Sciences
/ Humans
/ Induced Pluripotent Stem Cells - cytology
/ Induced Pluripotent Stem Cells - metabolism
/ letter
/ Mice
/ Poly (ADP-Ribose) Polymerase-1
/ Poly(ADP-ribose) Polymerases - genetics
/ Poly(ADP-ribose) Polymerases - metabolism
/ Proteins
/ Proto-Oncogene Proteins - metabolism
/ Receptors, Estrogen - genetics
/ Receptors, Estrogen - metabolism
/ Science
