MOF-associated complexes ensure stem cell identity and Xist repression.

Tomasz Chelmicki,Rolf Backofen,Tugce Aktas,Thomas Manke,Pavankumar Videm,Patrick Rudolf Wright,Anne-Valerie Gendrel,Edith Heard,Tasneem Khanam,Friederike Dündar,Fidel Ramírez,Asifa Akhtar,Matthew James Turley

doi:10.7554/elife.02024

Abstract

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.

Highlights

Histone acetyl transferases (HATs) are among the key architects of the cellular epigenetic landscape as the acetylation of histones is unanimously associated with transcriptionally active domains
MOF and its complexes show distinct chromatin binding dynamics during differentiation To examine the behavior of male-specific lethal (MSL) and non-specific lethal (NSL) proteins in a cell type-specific manner, we derived homogeneous populations of multipotent neuronal progenitor cells (NPCs) from mouse embryonic stem cells (ESCs) (Conti et al, 2005; Splinter et al, 2011; Gendrel et al, 2014)
MSL and NSL complex members showed distinct RNA and protein dynamics during the process of differentiation: KANSL1 and KANSL3 protein levels remained unchanged, whereas MSL1, MSL2 and MOF became more abundant in NPCs accompanied by increased H4K16 acetylation (H4K16ac) (Figure 1B)

Summary

Introduction

Histone acetyl transferases (HATs) are among the key architects of the cellular epigenetic landscape as the acetylation of histones is unanimously associated with transcriptionally active domains. Many HATs have the ability to acetylate non-histone proteins extending their influence to diverse cellular pathways inside and outside of the nucleus (reviewed in Sapountzi and Cote, 2011). Based on their catalytic domains, the HATs are classified into two major families, GCN5 N-acetyl transferases (GNATs) and MYST HATs (named after the founding members MOZ, Ybf2/Sas, Sas, Tip60), that encompass diverse sets of protein complexes. As part of the male-specific lethal (MSL) complex

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