The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming

Abstract

Induced pluripotent stem cells (iPSCs) can be derived from somatic cells by ectopic expression of different transcription factors, classically Oct4 (also known as Pou5f1), Sox2, Klf4 and Myc (abbreviated as OSKM). This process is accompanied by genome-wide epigenetic changes, but how these chromatin modifications are biochemically determined requires further investigation. Here we show in mice and humans that the histone H3 methylated Lys 27 (H3K27) demethylase Utx (also known as Kdm6a) regulates the efficient induction, rather than maintenance, of pluripotency. Murine embryonic stem cells lacking Utx can execute lineage commitment and contribute to adult chimaeric animals; however, somatic cells lacking Utx fail to robustly reprogram back to the ground state of pluripotency. Utx directly partners with OSK reprogramming factors and uses its histone demethylase catalytic activity to facilitate iPSC formation. Genomic analysis indicates that Utx depletion results in aberrant dynamics of H3K27me3 repressive chromatin demethylation in somatic cells undergoing reprogramming. The latter directly hampers the derepression of potent pluripotency promoting gene modules (including Sall1, Sall4 and Utf1), which can cooperatively substitute for exogenous OSK supplementation in iPSC formation. Remarkably, Utx safeguards the timely execution of H3K27me3 demethylation observed in embryonic day 10.5-11 primordial germ cells (PGCs), and Utx-deficient PGCs show cell-autonomous aberrant epigenetic reprogramming dynamics during their embryonic maturation in vivo. Subsequently, this disrupts PGC development by embryonic day 12.5, and leads to diminished germline transmission in mouse chimaeras generated from Utx-knockout pluripotent cells. Thus, we identify Utx as a novel mediator with distinct functions during the re-establishment of pluripotency and germ cell development. Furthermore, our findings highlight the principle that molecular regulators mediating loss of repressive chromatin during in vivo germ cell reprogramming can be co-opted during in vitro reprogramming towards ground state pluripotency.

Role of epigenetics in the etiology of germ cell cancer

“…Utx, an H3K27 demethylase, regulates efficient induction of pluripotency. In the absence of Utx, PGC showed aberrant, cell-autonomous germ cell development during their embryonic maturation in vivo, as well as aberrant epigenetic reprogramming (Mansour et al, 2012). CIS cells showed low levels of the repressive histone modifications H3K9me2 and H3K27me3, but high levels of activating marks H3K9Ac, H3K4me and H2A.Z (Almstrup et al, 2010).…”

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

“…iPSCs derived in the absence of Utx bear aberrant H3K27me3 and H3K4me3 profiles. Mechanistically, Utx specifically regulates a set of pluripotency genes, including Sall1, Sall4 and Utf1, whose activation is important for establishing pluripotency [110]. Although Utx is dispensable for ESC derivation and maintenance, Utx-deficient ESCs are crippled in differentiation [110,111].…”

“…Utx, an H3K27me3/2-specific demethylase, is required for efficient reprogramming in both cell fusion-mediated and transcription factors-induced reprogramming [110]. iPSCs derived in the absence of Utx bear aberrant H3K27me3 and H3K4me3 profiles.…”

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

“…These changes do not affect the nucleotide sequence but rather they alter other features such as the patterns of DNA methylation and histone modification that are inherited through cell divisions and across generations along with the genetic information [2,3]. One of the most fundamental roles of epigenetics is the guidance of cellular differentiation in development [4]. Cascades of gene expression changes that are directed by epigenetic processes explain how cells and tissues with dramatically different phenotypic features can arise given that they all carry common genetic material [5].…”