Biology subjects

Gharbi, S.

Publications and source records attributed to Gharbi, S..

3 recordsLinked to original sources

bioRxiv2018

MTA proteins act redundantly within the NuRD complex to ensure fidelity of ES cell lineage commitment

Multiprotein chromatin remodelling complexes show remarkable conservation of function amongst metazoans, even though components present in invertebrates are often present as multiple paralogous proteins in vertebrate complexes. In some cases these paralogues specify distinct biochemical and/or functional activities in vertebrate cells. Here we set out to define the biochemical and functional diversity encoded by one such group of proteins within the mammalian Nucleosome Remodelling and Deacetylation (NuRD) complex: Mta1, Mta2 and Mta3. We find that, in contrast to what has been described in somatic cells, MTA proteins are not mutually exclusive within ES cell NuRD and, despite subtle differences in chromatin binding and biochemical interactions, serve largely redundant functions. Nevertheless, ES cells lacking all three MTA proteins represent a complete NuRD null and are viable, allowing us to identify a previously undetected function for NuRD in maintaining differentiation trajectory during early stages of lineage commitment.

developmental biology↗

bioRxiv2017

Transcriptional control by Sall4 in blastocysts facilitates lineage commitment of inner cell mass cells

The enhancer-binding zinc finger transcription factor Sall4 is essential for early mammalian postimplantation development and plays important roles in lineage commitment of embryonic stem cells. Enhancer binding by Sall4 results in transcriptional activation of some genes, but repression of others. Exactly how cells in preimplantation stage embryos use this transcriptional modulatory activity of Sall4 during early developmental transitions has not been determined. Using single cell gene expression analyses we show that Sall4 is required to maintain the gene regulatory network in inner cell mass (ICM) cells prior to lineage commitment. Although Sall4 is not required for ICM cells to adopt a correct epiblast or primitive endoderm gene expression profile, in the absence of Sall4 early ICM cells commit to either lineage at reduced frequency. We propose a model whereby Sall4 activity sets the stage for efficient progression from the uncommitted ICM progenitor state by modulating the gene regulatory network in early ICM cells.

developmental biology↗

bioRxiv2017

The Nucleosome Remodelling and Deacetylation complex restricts Mediator access to enhancers to control transcription

A number of different chromatin remodelling complexes in mammalian cells are implicated in the control of gene expression. The genetic requirements for many such complex components have been described, and the biochemical activities of complex components characterised in vitro, yet the molecular mechanisms by which these biochemical activities impact transcriptional regulation in vivo remain ill-defined. Using an inducible system with fine temporal resolution, we show that the Nucleosome Remodelling and Deacetylation (NuRD) complex directly regulates chromatin architecture at enhancer regions in ES cells, in turn influencing the activity of RNA polymerase II via Mediator. Through this mechanism NuRD restricts Mediator access to enhancer chromatin during lineage commitment, thereby enabling appropriate transcriptional regulation. In contrast, acetylation levels of histone H3 lysine 27 are not immediately impacted by NuRD activity, correlating with transcriptional response only after expression levels have changed. These findings provide a detailed, molecular picture of genome-wide modulation of lineage-specific transcription by an abundant chromatin remodelling complex.

molecular biology↗