Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2

Department of Pathology, Taub Institute for Aging, Columbia University, New York, New York 10032, USA.
Nature (Impact Factor: 41.46). 08/2012; 488(7413):652-5. DOI: 10.1038/nature11333
Source: PubMed


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). 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). 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, our data, and also studies of Tet2-mutant human tumour cells, 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.

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Available from: Keiichi Inoue
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    • "However, ERRs are unable to activate target gene transcription in response to estrogens. Doege et al. (2012) described an essential role of ERR in somatic cell reprogramming and induction of transcription at endogenous pluripotency loci such as NANOG, OCT4, SOX2, KLF4 and MYC. Moreover, Luo et al. (1997) demonstrated that ERR is crucial for placental development as well as the death of homozygous null mutants due to defective diploid trophoblast proliferation. "
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    • "PARP1, localized primarily to the nucleus, is the most abundant family member in humans (Vyas et al., 2013; Wang et al., 2012) and has been mainly examined in the context of base excision repair (Sousa et al., 2012). Recently PARP1 was implicated in other DNA repair pathways as well as in pathways outside of DNA repair such as transcription (Ji and Tulin, 2013; Krishnakumar and Kraus, 2010b) and stem cell identity (Chiou et al., 2013; Doege et al., 2012; Ogino et al., 2007). The details of its involvement in any of these pathways remain poorly understood. "
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    • "The recent discovery of cytosine hydroxymethylation raises the possibility that methylation at CGIs can be reversed via active cytosine demethylation involving TET proteins leading to the reactivation of transcriptionally silenced promoters [9, 10]. Furthermore new evidence on induced pluripotent stem cells (iPSCs) suggests that the 5hmC base modification not only is an intermediate within cytosine demethylation, but acts as an epigenetic mark in itself, possibly aiding in recruitment of factors that promote chromatin remodeling [25, 26]. "
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