The Nucleosome Remodelling and Deacetylation complex suppresses transcriptional noise during lineage commitment

Abstract

Multiprotein chromatin remodelling complexes show remarkable conservation of function amongst metazoans, even though components present in invertebrates are often found 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 (Nu RD ) 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 embryonic stem (ES) cell Nu RD and, despite subtle differences in chromatin binding and biochemical interactions, serve largely redundant functions. ES cells lacking all three MTA proteins exhibit complete Nu RD loss of function and are viable, allowing us to identify a previously unreported function for Nu RD in reducing transcriptional noise, which is essential for maintaining a proper differentiation trajectory during early stages of lineage commitment.

Dynamic properties of noise and Her6 levels are optimized by miR‐9, allowing the decoding of the Her6 oscillator

“…Despite the intense interest in the biological role and consequences of protein expression noise (Eling et al , ), our understanding has been hampered by the lack of evidence of the dynamic properties of such noise. Indeed, with the exception of live study of transcriptional bursting, our current understanding of biological protein and gene expression noise is based on snapshot measurements of variability across populations, such as phenotypic or molecular variability of individuals and/or variability in molecular abundance between cells (often determined by scRNA seq), variability of fluorescence in single cells (reviewed in Eling et al , ) or simply the inappropriate re‐expression of genes (Burgold et al , ). Similarly, the effect of miRNAs in controlling noise has been based on artificial synthetic systems or analysis of static measurements (Li et al , ; Siciliano et al , ; Schmiedel et al , ).…”

Capture of mouse and human stem cells with features of formative pluripotency

“…We tested primitive streak-like induction in response to activin and GSK3 inhibition (Burgold et al, 2019). We observed substantially higher induction of mesendoderm surface markers and gene expression from FS cells than from EpiSCs ( Fig.…”

Nucleosome-CHD4 chromatin remodeler structure maps human disease mutations

“…NuRD is implicated in gene silencing, but also gene activation ( Gnanapragasam et al, 2011 ). It is essential for cell cycle progression ( Polo et al, 2010 ), DNA damage response ( Larsen et al, 2010 ; Smeenk et al, 2010 ), establishment of heterochromatin ( Sims and Wade, 2011 ), and differentiation ( Bornelöv et al, 2018 ; Burgold et al, 2019 ). In addition, CHD4 is part of the heterotrimeric ChAHP complex that is also involved in gene repression ( Ostapcuk et al, 2018 ).…”