TY - JOUR
T1 - The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming
AU - Mansour, Abed Al-Fatah
AU - Gafni, Ohad
AU - Weinberger, Leehee
AU - Zviran, Asaf
AU - Ayyash, Muneef
AU - Rais, Yoach
AU - Krupalnik, Vladislav
AU - Zerbib, Mirie
AU - Maza, Itay
AU - Geula, Shay
AU - Viukov, Sergey
AU - Holtzman, Liad
AU - Pribluda, Ariel
AU - Canaani, Eli
AU - Horn-Saban, Shirley
AU - Amit, Ido
AU - Novershtern, Noa
AU - Hanna, Jacob H.
N1 - ERC starting investigator grant [StG-2011-281906]; Israel Science Foundation Regular and Bikura research grants; ICRF Foundation; Fritz Thyssen Stiftung; Alon Foundation; E. A. and R. Drake, and the Leona M. and Harry B. Helmsley Charitable Trust; Weizmann Dean fellowship awardsJ.H.H. is supported by a generous gift from Ilana and Pascal Mantoux, The Sir Charles Clore Research Prize, an ERC starting investigator grant (StG-2011-281906), the Israel Science Foundation Regular and Bikura research grants, the ICRF Foundation, Fritz Thyssen Stiftung, the Alon Foundation scholar award, a grant from E. A. and R. Drake, and the Leona M. and Harry B. Helmsley Charitable Trust. N.N. and A. P. are supported by Weizmann Dean fellowship awards. We thank A. Smith, H. Niwa and M. Saitou for reagents. We thank the Weizmann Institute management for providing critical financial and infrastructural support.
PY - 2012/8
Y1 - 2012/8
N2 - 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)(1). This process is accompanied by genome-wide epigenetic changes(2-5), 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(6-9) (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 germcells (PGCs)(10), and Utx-deficientPGCs 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
AB - 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)(1). This process is accompanied by genome-wide epigenetic changes(2-5), 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(6-9) (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 germcells (PGCs)(10), and Utx-deficientPGCs 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
U2 - https://doi.org/10.1038/nature11272
DO - https://doi.org/10.1038/nature11272
M3 - مقالة
SN - 0028-0836
VL - 488
SP - 409-+
JO - Nature
JF - Nature
IS - 7411
ER -