ADP-ribosyltransferases Parp1 and Parp7 safeguard pluripotency of ES cells

Abstract

Embryonic stem (ES) cells are in a dynamic equilibrium of distinct functional states, characterized by the heterogeneous expression of critical pluripotency factors and regulated by a spectrum of reversible histone modifications. Maintenance of this equilibrium is a hallmark of pluripotency. Here we find that the ADP-ribosyltransferases Parp1 and Parp7 play a critical role in safeguarding this state by occupying key pluripotency genes, notably Nanog, Pou5f1, Sox2, Stella, Tet1 and Zfp42, thereby protecting them from progressive epigenetic repression. In the absence of either Parp1 or Parp7, or upon inhibition of the ADP-ribosylating activity, ES cells exhibit a decrease in ground state pluripotency as they cannot maintain the typical heterogeneity characteristic of the metastable state. As a consequence, they display a higher propensity to differentiate. These findings place Parp1 and Parp7 at the genetic-epigenetic interface of pluripotency networks, fine-tuning the transcriptional heterogeneity and thereby determining the developmental plasticity of ES cells.

Global Transcriptome Analysis Reveals That Poly(ADP-Ribose) Polymerase 1 Regulates Gene Expression through EZH2

“…Because PARP1 regulates EZH2 functions, PARP1 activity may also be involved in EZH2-regulated processes. For example, a recent work demonstrated a key role for PARP1 activity in regulating the pluripotency of embryonic stem cells (45). Consistent with our results, in this work, PARP1 activity was necessary to maintain an active chromatin state at pluripotent genes and prevented the accumulation of H3K27me3 (45).…”

“…For example, a recent work demonstrated a key role for PARP1 activity in regulating the pluripotency of embryonic stem cells (45). Consistent with our results, in this work, PARP1 activity was necessary to maintain an active chromatin state at pluripotent genes and prevented the accumulation of H3K27me3 (45). Further support for the functional regulation of EZH2 by PARP is provided by the importance of the interaction of PARP3 and EZH2 and their colocalization with H3K27me3 during development in zebrafish (46,47).…”

Loss of the Mono-ADP-ribosyltransferase, Tiparp, Increases Sensitivity to Dioxin-induced Steatohepatitis and Lethality

“…T-cell function is regulated via ADP-ribosylation, and Tiparp expression is induced in response to viral infection (49). Tiparp has also been reported to safeguard the pluripotency of ES cells (50). It will be important to determine the extent to which other Ahr-regulated pathways are influenced by the induction of Tiparp and/or its activity.…”

“…Acute lethality to dioxin varies among species and within rodent strains. For example, the lethal dose 50 (LD 50 ) for guinea pigs, one of the most sensitive species, is 1-2 g/kg bw dioxin, whereas the LD 50 for hamsters is Ͼ5000 g/kg bw (12,15). In most strains of mice, lethality occurs only 2 or 3 weeks after a single dose of 114 -300 g/kg of dioxin, and it is associated with inhibition of gluconeogenesis but also with feed intake refusal and body weight loss (12,15).…”

Poly(ADP-Ribose) Polymerases in Aging - Friend or Foe?

“…Importantly, PARP-1 and PARP-7 define in stem cells whether cells undergo terminal differentiation or renewal [59].…”