MOF-associated complexes ensure stem cell identity and Xist repression.
Histone acetyl transferases (HATs) play distinct roles in many cellular processes and are frequently misregulated in cancers. Here, we study the regulatory potential of MYST1-(MOF)-containing MSL and NSL complexes in mouse embryonic stem cells (ESCs) and neuronal progenitors. We find that both complexes influence transcription by targeting promoters and TSS-distal enhancers. In contrast to flies, the MSL complex is not exclusively enriched on the X chromosome, yet it is crucial for mammalian X chromosome regulation as it specifically regulates Tsix, the major repressor of Xist lncRNA. MSL depletion leads to decreased Tsix expression, reduced REX1 recruitment, and consequently, enhanced accumulation of Xist and variable numbers of inactivated X chromosomes during early differentiation. The NSL complex provides additional, Tsix-independent repression of Xist by maintaining pluripotency. MSL and NSL complexes therefore act synergistically by using distinct pathways to ensure a fail-safe mechanism for the repression of X inactivation in ESCs.DOI: http://dx.doi.org/10.7554/eLife.02024.001.
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
Tomasz
T
Chelmicki
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany Bioinformatics Department, Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.
Friederike
F
Dündar
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
Matthew James
MJ
Turley
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Tasneem
T
Khanam
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Tugce
T
Aktas
Bioinformatics Department, Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.
Fidel
F
Ramírez
Mammalian Developmental Epigenetics Group, Institute Curie, Paris, France.
Anne-Valerie
AV
Gendrel
Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany.
Patrick Rudolf
PR
Wright
Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany.
Pavankumar
P
Videm
Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany BIOSS Center for Biological Signalling Studies, University of Freiburg, Freiburg, Germany Center for Biological Systems Analysis, University of Freiburg, Freiburg, Germany Center for Non-Coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, Denmark.
Rolf
R
Backofen
Mammalian Developmental Epigenetics Group, Institute Curie, Paris, France.
Edith
E
Heard
Bioinformatics Department, Max Planck Institute for Immunobiology and Epigenetics, Freiburg, Germany.
Thomas
T
Manke
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany akhtar@ie-freiburg.mpg.de.
Asifa
A
Akhtar
D000818:Animals; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D049951:X Chromosome Inactivation
D002843:Chromatin; D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA; D051548:Histone Acetyltransferases; C000622683:Kat8 protein, mouse
D. melanogaster; X inactivation; acetylation; chromatin; epigenetics; transcription