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

Abstract

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 contexts5–7, our data, and also studies of Tet2-mutant human tumour cells8, 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.

CHD1L Regulated PARP1-Driven Pluripotency and Chromatin Remodeling During the Early-Stage Cell Reprogramming

“…Our group and others have recently demonstrated that PARP1 is also involved in the efficient generation of iPSCs, which is probably due to PARP1‐dependent chromatin remodeling and epigenetic modulation 8, 11, 27. Here, we established strong physical and functional links between PARP1 and CHD1L and their roles in regulating the chromatin states of stemness genes.…”

“…In addition, PARP1 occupies gene loci such as Nanog and Esrrb to enrich activation‐associated marker histone H3 lysine 4 dimethylation (H3K4me2) in early‐stage reprogramming 11, 30. In addition to our observation that PARP1 interacts with CHD1L, it is plausible that CHD1L may also coregulate the chromatin status of stemness genes, such as Pou5f1, Nanog , and Esrrb , through an interaction with PARP1.…”

Role of epigenetics in the etiology of germ cell cancer

“…Technological advances have allowed the mapping of diverse histone modifications in a large number of cell types (Doege et al, 2012, Ferguson et al, 2012, Shahhoseini et al, 2010. In this context a number of relevant DNA segments must be recognized, which will be discussed in more detail in the next paragraphs.…”

Poly(ADP-ribose) polymerase 1 regulates nuclear reprogramming and promotes iPSC generation without c-Myc

“…2). In addition, Doege, et al (2012) recently reported that Parp1 and TeT2 serve essential roles in the regulation of epigenetic markers and the chromatin state at Nanog and Essrb during somatic cell reprogramming. Importantly, Parp1 induction further promotes Oct4 repro gramming factor binding to the pluripotency loci of Nanog and Essrb.…”

“…It was previously demonstrated that Parp1 is a regulator of Sox2 (Gao et al, 2009;Lai et al, 2012), and it is involved in the efficient generation of iPSCs (Lai et al, 2012). Recently, Doege et al (2012) reported that Parp1 and TeT2 contribute to early stage epigenetic modification during somatic cell reprogramming, and the induction of the Parp1 gene further promotes accessibility to the pluripotency factor Oct4. Therefore, it is conceivable that Parp1 and PARylation may be involved in the regulation of nuclear reprogramming or the maintenance of pluripotent properties in stem cells.…”