Differential regulation of lineage commitment in human and mouse primed pluripotent stem cells by the nucleosome remodelling and deacetylation complex.

Ramy Ragheb,Julie Cramard,Thomas Burgold,Brian Hendrich,Nicola Reynolds,Sarah Gharbi,Michiel Vermeulen,Susan L Kloet,Oluwaseun Ogundele

doi:10.1016/j.scr.2020.101867

Abstract

Differentiation of mammalian pluripotent cells involves large-scale changes in transcription and, among the molecules that orchestrate these changes, chromatin remodellers are essential to initiate, establish and maintain a new gene regulatory network. The Nucleosome Remodelling and Deacetylation (NuRD) complex is a highly conserved chromatin remodeller which fine-tunes gene expression in embryonic stem cells. While the function of NuRD in mouse pluripotent cells has been well defined, no study yet has defined NuRD function in human pluripotent cells. Here we find that while NuRD activity is required for lineage commitment from primed pluripotency in both human and mouse cells, the nature of this requirement is surprisingly different. While mouse embryonic stem cells (mESC) and epiblast stem cells (mEpiSC) require NuRD to maintain an appropriate differentiation trajectory as judged by gene expression profiling, human induced pluripotent stem cells (hiPSC) lacking NuRD fail to even initiate these trajectories. Further, while NuRD activity is dispensable for self-renewal of mESCs and mEpiSCs, hiPSCs require NuRD to maintain a stable self-renewing state. These studies reveal that failure to properly fine-tune gene expression and/or to reduce transcriptional noise through the action of a highly conserved chromatin remodeller can have different consequences in human and mouse pluripotent stem cells.

Highlights

The identity of a eukaryotic cell is determined by its transcriptional output
Comparison of mass spectrometry data between human induced pluripotent stem cells (hiPSC), mouse epiblast stem cells (mEpiSCs) and mouse naïve ES cells (using MTA1-3 proteins for Nucleosome Remodelling and Deacetylation (NuRD) purification: (Burgold et al, 2019)) showed that most interacting proteins identified in human cells interact with mouse NuRD (Fig. 1C)
Two cell-type specific interactors are VRTN and ZNF423, both of which are not expressed in naïve ES cells, but are found interacting with NuRD in primed PSCs

Summary

Introduction

The identity of a eukaryotic cell is determined by its transcriptional output. The process by which cells transition from one state to another is necessarily subject to tight transcriptional controls. During development, in the absence of changes in external cues, transcriptional programs must remain stable for the identity of that cell to be maintained. Upon changes in external signals, transcription of some genes must be downregulated while that of others must be increased and this results in a change in cellular identity. The mechanisms which act either to maintain or change the expression state of a cell underlie the ordered progression of transitions that occur throughout embryonic development. Failure of regulation of these gene expression patterns can prevent successful execution of developmental decisions, leading to developmental abnormalities, tumorigenesis or death. A comprehensive understanding of how cells control transcription during cell fate decisions is critical for fields where it is desirable to control or instruct cell fate decisions, such as in regenerative medicine or cancer biology

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