The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression

Bornelöv, Susanne; Reynolds, Nicola; Xenophontos, Maria; Gharbi, Sarah; Johnstone, Ewan; Floyd, Robin; Ralser, Markus; Signolet, Jason; Loos, Remco; Dietmann, Sabine; Bertone, Paul; Hendrich, Brian

doi:10.1016/j.molcel.2018.06.003

Cited by 145 publications

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“…Sites found associated with all three MTA proteins were highly enriched for Chd4 and Mbd3 binding, consistent with these being core NuRD binding regions (Fig D). These sites were also enriched for marks of active promoters (H3K4Me3, H3K27Ac) and active enhancers (H3K4Me1, H3K27Ac, P300; Fig D and E), both of which are hallmarks of NuRD‐associated regions (Miller et al , ; Bornelöv et al , ). The same was true for sites bound by any two of the three MTA proteins (Fig EV2B).…”

Section: Resultsmentioning

confidence: 91%

“…Mta1 and Mta2 both contain two distinct RBBP interaction domains, while Mta3 lacks the C‐terminal most RBBP interaction domain (Millard et al , ). The Mta1 and Mta2 proteins show minimal loss of stability in the absence of Mbd3, but Mta3 requires an interaction with Mbd3 to be completely stable (Fig EV4B; Bornelöv et al , ). It is possible that the additional interaction with an Rbbp protein confers stability to Mta1 and Mta2 in the absence of Mbd3.…”

Section: Discussionmentioning

confidence: 96%

“…NuRD is highly conserved amongst metazoans and has been shown to play important roles in cell fate decisions in a wide array of systems (Denslow & Wade, ; Signolet & Hendrich, ). For example, in embryonic stem (ES) cells, NuRD controls nucleosome positioning at regulatory sequences to finely tune gene expression (Reynolds et al , ; Bornelöv et al , ), and in somatic lineages, NuRD activity has been shown to prevent inappropriate expression of lineage‐specific genes to ensure fidelity of somatic lineage decisions (Denner & Rauchman, ; Knock et al , ; Gomez‐Del Arco et al , ; Loughran et al , ). It was recently demonstrated that this is achieved in both ES cells and B‐cell progenitors by restricting access of transcription factors to regulatory sequences (Liang et al , ; Loughran et al , ; Bornelöv et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…For example, in embryonic stem (ES) cells, NuRD controls nucleosome positioning at regulatory sequences to finely tune gene expression (Reynolds et al , ; Bornelöv et al , ), and in somatic lineages, NuRD activity has been shown to prevent inappropriate expression of lineage‐specific genes to ensure fidelity of somatic lineage decisions (Denner & Rauchman, ; Knock et al , ; Gomez‐Del Arco et al , ; Loughran et al , ). It was recently demonstrated that this is achieved in both ES cells and B‐cell progenitors by restricting access of transcription factors to regulatory sequences (Liang et al , ; Loughran et al , ; Bornelöv et al , ). Additionally, aberrations in expression levels of NuRD component proteins are increasingly being linked to cancer progression (Lai & Wade, ; Mohd‐Sarip et al , ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…The Ikaros family of TFs (including aiolos) play important roles in lymphocyte development and are often associated with the NuRD complex, an ATPdependent chromatin-remodelling complex involved in transcriptional repression. [13,14] Our DNA pull-down approach identified most of the components of the NuRD complex active at this locus (CHD4, MBD2, RBBP4, HDAC1, HDAC2 and KDM1A), all of which exhibit the same preferential binding to the A allele. Results consistent with these were also obtained by WB, EMSA and ChIP-qPCR, suggesting that transcriptional repression [7] associated with the NuRD complex is implicated in the pathogenesis of AS perhaps by regulating RUNX3 expression in CD8+ T-cells.…”

Section: Discussion (643)mentioning

confidence: 99%

A RUNX3 enhancer polymorphism associated with ankylosing spondylitis influences recruitment of Interferon Regulatory Factor 5 and factors of the Nucleosome Remodelling Deacetylase Complex in CD8+ T-cells

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Objectives:To investigate the functional consequences of the single nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter strongly associated with ankylosing spondylitis (AS). Methods:The effects of rs4648889 on transcription factor (TF) binding were tested by DNA pull-down and quantitative mass spectrometry. The results were validated by electrophoretic mobility gel shift assays (EMSA), Western blot (WB) analysis of the pulled-down eluates, and chromatin immuno-precipitation (ChIP)-qPCR.Results: Several TFs showed differential allelic binding to a 50bp DNA probe spanning rs4648889. Binding was increased to the AS-risk A allele for IKZF3 (aiolos) in nuclear extracts from CD8+ T-cells (3.7-fold, p<0.03) and several components of the NUcleosome Remodeling Deacetylase (NuRD) complex, including Chromodomain-Helicase-DNA-binding protein 4 (3.6-fold, p<0.05) and Retinoblastoma-Binding Protein 4 (4.1-fold, p<0.02). In contrast, binding of interferon regulatory factor (IRF) 5 was increased to the AS-protective G allele. These results were confirmed by EMSA, WB and ChIP-qPCR. Conclusions:The association of AS with rs4648889 most likely results from its influence on the binding of this enhancer-like region to TFs, including IRF5, IKZF3 and members of the NuRD complex. Further investigation of these factors and RUNX3-related pathways may reveal important new therapeutic possibilities in AS. Word count: 196Total word count: 1459 (All Methods online)

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Rise of the Chromodomain Helicase DNA‐Binding (CHD) Chromatin Remodelling Machines

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Vital processes such as transcription, repair, replication and recombination continuously shape cellular chromatin landscape. The chromodomain helicase DNA‐binding (CHD) family of enzymes regulate chromatin dynamics by utilising energy from ATP hydrolysis to alter nucleosomal position, structure and composition, thereby modulating accessibility of the underlying DNA sequence. The CHD enzymes are highly conserved in evolution, and genetic studies in fungi, plants and animals demonstrate their critical roles in regulation of cellular identity and fate and organismal development. Advances in genomic studies over the past two decades led to the identification of frequent DNA copy‐number alterations, mutations and aberrant expression of CHDs in human malignancies and various disorders, highlighting their importance as relevant biomarkers or targets for therapeutic intervention. Key Concepts CHD family of enzymes (CHD1‐9) are evolutionary conserved ATP‐dependent chromatin remodelers that mobilise nucleosomes to regulate DNA‐templated processes, such as transcription, replication and repair. They are critical for normal organismal development and are frequently mutated in human disorders and cancers. Chromodomain helicase DNA‐binding proteins (CHD1‐9) are evolutionary conserved family of ATP‐dependent chromatin remodelers that mobilise nucleosomes to regulate DNA‐templated processes such as transcription, replication and DNA repair. CHD enzymes share a common domain structure: two N‐terminal chromodomains, a central ATPase/helicase domain, and a C‐terminal DNA‐binding domain. CHD proteins play crucial roles in diverse cellular processes, including embryonic development, stem cell maintenance and differentiation, and tissue‐specific gene expression. Dysregulation of CHD proteins has been associated with various human diseases, including cancer and neurodevelopmental disorders. CHD proteins are attractive targets for the development of new therapies for diseases associated with chromatin dysfunction. Understanding the molecular mechanisms underlying the function of CHD proteins may pave the way for the development of new drugs that target these proteins and improve the treatment of a variety of human diseases.

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The Nucleosome Remodeling and Deacetylation Complex Modulates Chromatin Structure at Sites of Active Transcription to Fine-Tune Gene Expression

Cited by 145 publications

References 53 publications

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

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

A RUNX3 enhancer polymorphism associated with ankylosing spondylitis influences recruitment of Interferon Regulatory Factor 5 and factors of the Nucleosome Remodelling Deacetylase Complex in CD8+ T-cells

Rise of the Chromodomain Helicase DNA‐Binding (CHD) Chromatin Remodelling Machines

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