The Nucleosome Remodeling and Deacetylase Chromatin Remodeling (NuRD) Complex Is Required for Peripheral Nerve Myelination

AbstractTestis development and sustained germ cell production in adults rely on the establishment of spermatogonia stem cells and their proper differentiation into mature gametes. Control of these processes involves not only promoting the expression of genes required for cell survival and differentiation but also repressing other cell fates. This level of transcriptional control requires chromatin-remodeling complexes that restrict or promote transcription machinery. Here, we investigated the roles of the NUcleosome Remodeling and Deacetylase (NURD) complex during spermatogenesis. Our cellular and biochemical analyses revealed differential expression and composition of NURD subunits in gametocytes at different stages of testis development. Germ cell-specific deletion of the NURD catalytic component CHD4, but not CHD3, resulted in arrested early gamete development due to failed cell survival of the undifferentiated spermatogonia stem cell population. Genome-wide CHD4 chromatin localization and transcriptomic analyses revealed that CHD4 binds the promoters and regulates the expression of genes involved in spermatogonia cell survival and differentiation. These results uncover the requirements of CHD4 in mammalian gonad development, and point to unique roles for the NURD complex with respect to other chromatin remodelers during gamete development.Significance StatementGametogenesis is a fundamental developmental program required for sustained fertility and survival of all sexually reproducing species. The developing male gamete undergoes numerous cell divisions and developmental stage transitions that are carefully monitored by epigenetic mechanisms. One prominent mechanism is directed by chromatin remodeling complexes, which modify chromatin structure and thereby control fundamental cellular processes such as gene transcription. In this work, we focused in understanding the role of CHD4 and CHD3 proteins, catalytic subunits of the NURD chromatin-remodeling complex, in mouse gametogenesis. We find that CHD4 has an essential function in gametogenesis, with an absolute requirement for survival of spermatogonia populations in the developing testis. This is accompanied by CHD4-mediated transcriptional regulation of genes important for spermatogonia survival, and differentiation.

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Unique Protein Interaction Networks Define The Chromatin Remodeling Module of The NuRD Complex

10.1101/2021.01.27.428018 ◽

2021 ◽

Author(s):

Mehdi Sharifi Tabar ◽

Caroline Giardina ◽

Yue Julie Feng ◽

Habib Francis ◽

Hakimeh Moghaddas Sani ◽

...

Keyword(s):

Chromatin Remodeling ◽

Protein Interaction ◽

Treatment Strategies ◽

Interaction Network ◽

Terminal Segment ◽

Mass Spectrometry Analysis ◽

Nurd Complex ◽

Nucleosome Remodeling ◽

Spectrometry Analysis ◽

Underlying Mechanisms

AbstractThe combination of four proteins and their paralogues including MBD2/3, GATAD2A/B, CDK2AP1, and CHD3/4/5, which we refer to as the MGCC module, form the chromatin remodeling module of the Nucleosome Remodeling and Deacetylase (NuRD) complex, a gene repressor complex. Specific paralogues of the MGCC subunits such as MBD2 and CHD4 are amongst the key repressors of adult-stage fetal globin and provide important targets for molecular therapies in beta (β)-thalassemia. However, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed to date. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential in defining underlying mechanisms and developing treatment strategies. Therefore, using pulldown followed by mass spectrometry analysis (PD-MS) we report a proteome-wide interaction network of the MGCC module in a paralogue-specific manner. Our data also demonstrate that the disordered C-terminal region of CHD3/4/5 is a gateway to incorporate remodeling activity into both the ChAHP (CHD4, ADNP, HP1γ) and NuRD complexes in a mutually exclusive manner. We define a short aggregation prone region (APR) within the C-terminal segment of GATAD2B that is essential for the interaction of CHD4 and CDK2AP1 with the NuRD complex. Finally, we also report an association of CDK2AP1 with the Nuclear Receptor Co-Repressor (NCOR) complex. Overall, this study provides insight into the possible mechanisms through which the MGCC module can achieve specificity and diverse biological functions.

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HDAC1 SUMOylation promotes Argonaute directed transcriptional silencing in C. elegans

10.1101/2020.08.17.254466 ◽

2020 ◽

Author(s):

Heesun Kim ◽

Yue-He Ding ◽

Gangming Zhang ◽

Yong-Hong Yan ◽

Darryl Conte ◽

...

Keyword(s):

Chromatin Remodeling ◽

De Novo ◽

Transcriptional Silencing ◽

Nurd Complex ◽

Nucleosome Remodeling ◽

C Elegans ◽

Argonaute Proteins ◽

Associated Proteins ◽

Heterochromatin Silencing

SUMMARYEukaryotic cells use guided search to coordinately control dispersed genetic elements. The transitive effectors of these mechanisms, Argonaute proteins and their small-RNA co-factors, engage nascent RNAs and chromatin-associated proteins to direct transcriptional silencing. The small ubiquitin-like modifier (SUMO) has been shown to promote the induction and maintenance of silent chromatin (called heterochromatin) in yeast, plants, and animals. Here we show that Argonaute-directed transcriptional silencing in C. elegans requires SUMOylation of the type 1 histone deacetylase HDA-1. SUMOylation of HDA-1 promotes interactions with components of the nucleosome remodeling and deacetylase (NuRD) complex and with the nuclear Argonaute HRDE-1/WAGO-9. Our findings suggest how HDAC1 SUMOylation promotes the association of HDAC and other chromatin remodeling factors with a nuclear Argonaute in order to initiate de novo heterochromatin silencing.

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GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors

10.21203/rs.3.rs-540714/v1 ◽

2021 ◽

Author(s):

Anne Helness ◽

Jennifer Fraszczak ◽

Charles Joly-Beauparlant ◽

Halil Bagci ◽

Christian Trahan ◽

...

Keyword(s):

Chromatin Remodeling ◽

Target Genes ◽

Myeloid Differentiation ◽

Open Chromatin ◽

Nurd Complex ◽

Active Chromatin ◽

Nucleosome Remodeling ◽

Nucleosome Organization ◽

Active Transcription ◽

Neutrophil Differentiation

Abstract GFI1 is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation, in particular the formation of neutrophils. Here we show that GFI1 interacts with the chromodomain helicase CHD4 and other components of the “Nucleosome remodeling and deacetylase” (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites of open chromatin enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes that are regulated by active or bivalent promoters and active enhancers. Our data also show that GFI1 and GFI1/CHD4 complexes occupy promoters of different sets of genes that are either enriched for IRF1 or SPI-1 consensus sites, respectively. During neutrophil differentiation, overall chromatin closure and depletion of H3K4me2 occurs at different degrees depending on whether GFI1, CHD4 or both are present, indicating that GFI1 affects the chromatin remodeling activity of the NuRD complex. Moreover, GFI1/CHD4 complexes regulate chromatin openness and histone modifications differentially to enable regulation of target genes affecting the signaling pathways of the immune response or nucleosome organization or cellular metabolic processes.

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Chromatin Remodeling Proteins Interact with Pericentrin to Regulate Centrosome Integrity

Molecular Biology of the Cell ◽

10.1091/mbc.e06-07-0604 ◽

2007 ◽

Vol 18 (9) ◽

pp. 3667-3680 ◽

Cited By ~ 26

Author(s):

James Edward Sillibourne ◽

Bénédicte Delaval ◽

Sambra Redick ◽

Manisha Sinha ◽

Stephen John Doxsey

Keyword(s):

Rna Interference ◽

Chromatin Remodeling ◽

Chromosome Segregation ◽

Time Lapse ◽

Dna Binding Protein ◽

Nurd Complex ◽

Yeast Two Hybrid ◽

Nucleosome Remodeling ◽

Time Lapse Imaging ◽

Two Hybrid

Pericentrin is an integral centrosomal component that anchors regulatory and structural molecules to centrosomes. In a yeast two-hybrid screen with pericentrin we identified chromodomain helicase DNA-binding protein 4 (CHD4/Mi2β). CHD4 is part of the multiprotein nucleosome remodeling deacetylase (NuRD) complex. We show that many NuRD components interacted with pericentrin by coimmunoprecipitation and that they localized to centrosomes and midbodies. Overexpression of the pericentrin-binding domain of CHD4 or another family member (CHD3) dissociated pericentrin from centrosomes. Depletion of CHD3, but not CHD4, by RNA interference dissociated pericentrin and γ-tubulin from centrosomes. Microtubule nucleation/organization, cell morphology, and nuclear centration were disrupted in CHD3-depleted cells. Spindles were disorganized, the majority showing a prometaphase-like configuration. Time-lapse imaging revealed mitotic failure before chromosome segregation and cytokinesis failure. We conclude that pericentrin forms complexes with CHD3 and CHD4, but a distinct CHD3–pericentrin complex is required for centrosomal anchoring of pericentrin/γ-tubulin and for centrosome integrity.

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GFI1 tethers the NuRD complex to open and transcriptionally active chromatin in myeloid progenitors

10.1101/2021.05.31.446398 ◽

2021 ◽

Author(s):

Tarik Moroy ◽

Anne Helness ◽

Jennifer Fraszczak ◽

Charles Joly-Beauparlant ◽

Halil Bagci ◽

...

Keyword(s):

Chromatin Remodeling ◽

Target Genes ◽

Myeloid Differentiation ◽

Open Chromatin ◽

Nurd Complex ◽

Active Chromatin ◽

Nucleosome Remodeling ◽

Nucleosome Organization ◽

Active Transcription ◽

Neutrophil Differentiation

GFI1 is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation, in particular the formation of neutrophils. Here we show that GFI1 interacts with the chromodomain helicase CHD4 and other components of the "Nucleosome remodeling and deacetylase" (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites of open chromatin enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes that are regulated by active or bivalent promoters and active enhancers. Our data also show that GFI1 and GFI1/CHD4 complexes occupy promoters of different sets of genes that are either enriched for IRF1 or SPI-1 consensus sites, respectively. During neutrophil differentiation, overall chromatin closure and depletion of H3K4me2 occurs at different degrees depending on whether GFI1, CHD4 or both are present, indicating that GFI1 affects the chromatin remodeling activity of the NuRD complex. Moreover, GFI1/CHD4 complexes regulate chromatin openness and histone modifications differentially to enable regulation of target genes affecting the signaling pathways of the immune response or nucleosome organization or cellular metabolic processes.

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The Expanding Mi-2/NuRD Complexes: A Schematic Glance

Proteomics Insights ◽

10.4137/pri.s6329 ◽

2010 ◽

Vol 3 ◽

pp. PRI.S6329 ◽

Cited By ~ 2

Author(s):

Yue Zhang ◽

Yinghua Li

Keyword(s):

Chromatin Remodeling ◽

Normal Development ◽

Model Organism ◽

Control Gene ◽

Nurd Complex ◽

Specific Context ◽

Nucleosome Remodeling ◽

Therapeutic Implications ◽

And Function ◽

Control Gene Activity

This mini-review will schematically update the progress of the expanding Mi-2/Nucleosome Remodeling Deacetylase (NuRD) complexes in cancer and in normal development such as stemness, with a focus on mammals and the increasingly popular and powerful model organism Caenorhabditis elegans. The Mi-2/NuRD complexes control gene activity during the development of complex organisms. Every Mi-2/NuRD complex contains many different core polypeptides, which form distinct multifunctional complexes with specific context-dependent regulators. The Mi-2/NuRD complexes have unique ATP-dependent chromatin remodeling, histone deacetylase, demethylase activities and higher order chromatin organization. They can regulate the accessibility of transcription factors or repair proteins to DNA. In this review, we summarize our current knowleges in the composition, interaction and function of the subunits within the Mi-2/NuRD complex, the methodology used for the identification of Mi-2/NuRD complexes, as well as the clinical and therapeutic implications targeting the Mi-2/NuRD subunits.

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Chromatin Remodeling in the Brain-a NuRDevelopmental Odyssey

International Journal of Molecular Sciences ◽

10.3390/ijms22094768 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4768

Author(s):

Sarah Larrigan ◽

Sujay Shah ◽

Alex Fernandes ◽

Pierre Mattar

Keyword(s):

Brain Development ◽

Chromatin Remodeling ◽

Neural Progenitors ◽

Nurd Complex ◽

Glial Differentiation ◽

Nucleosome Remodeling ◽

Chromatin Remodeling Complexes ◽

Genetic Level ◽

The Brain

During brain development, the genome must be repeatedly reconfigured in order to facilitate neuronal and glial differentiation. A host of chromatin remodeling complexes facilitates this process. At the genetic level, the non-redundancy of these complexes suggests that neurodevelopment may require a lexicon of remodelers with different specificities and activities. Here, we focus on the nucleosome remodeling and deacetylase (NuRD) complex. We review NuRD biochemistry, genetics, and functions in neural progenitors and neurons.

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ZBTB2 protein is a new partner of the Nucleosome Remodeling and Deacetylase (NuRD) complex

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2020.12.029 ◽

2021 ◽

Vol 168 ◽

pp. 67-76

Author(s):

Rosita Russo ◽

Veronica Russo ◽

Francesco Cecere ◽

Mariangela Valletta ◽

Maria Teresa Gentile ◽

...

Keyword(s):

Nurd Complex ◽

Nucleosome Remodeling

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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

10.1101/832840 ◽

2019 ◽

Author(s):

Matteo Vecellio ◽

Adrian Cortes ◽

Sarah Bonham ◽

Carlo Selmi ◽

Julian C Knight ◽

...

Keyword(s):

T Cells ◽

Ankylosing Spondylitis ◽

Cd8 T Cells ◽

Binding Protein ◽

Interferon Regulatory Factor ◽

Regulatory Factor ◽

Nurd Complex ◽

Nucleosome Remodeling ◽

Nuclear Extracts ◽

Functional Consequences

ABSTRACTObjectivesTo 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).MethodsThe 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.ResultsSeveral 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.ConclusionsThe 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.

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