scholarly journals MBD3, a Component of the NuRD Complex, Facilitates Chromatin Alteration and Deposition of Epigenetic Marks

2008 ◽  
Vol 28 (19) ◽  
pp. 5912-5923 ◽  
Author(s):  
Lluis Morey ◽  
Carmen Brenner ◽  
Francesco Fazi ◽  
Raffaella Villa ◽  
Arantxa Gutierrez ◽  
...  
Keyword(s):  
Histone Methylation ◽  
Chromatin Structure ◽  
Target Genes ◽  
Histone Deacetylation ◽  
Leukemic Cells ◽  
Nurd Complex ◽  
Global Methylation ◽  
Functional Link ◽  
Nucleosome Remodeling ◽  
Epigenetic Marks

ABSTRACT In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodeling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PML-RARa represses target genes through recruitment of DNA methytransferases and Polycomb complex. Here, we demonstrate a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leukemia (APL). We show that PML-RARa binds and recruits NuRD to target genes, including to the tumor-suppressor gene RARβ2. In turn, the NuRD complex facilitates Polycomb binding and histone methylation at lysine 27. Retinoic acid treatment, which is often used for patients at the early phase of the disease, reduced the promoter occupancy of the NuRD complex. Knockdown of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction but also impaired DNA and histone methylation, as well as stable silencing, thus favoring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis that could be exploited for therapeutic intervention.

scholarly journals Identification of proteins that can participate in the recruitment of Ttk69 to genomic sites of Drosophila melanogaster

2019 ◽  
Vol 23 (2) ◽  
pp. 180-183
Author(s):  
I. S. Osadchiy ◽  
T. N. Fedorova ◽  
P. G. Georgiev ◽  
O. G. Maksimenko
Keyword(s):  
Dna Binding ◽  
Target Genes ◽  
Regulatory Elements ◽  
Binding Activity ◽  
Histone Deacetylation ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
Dna Binding Activity ◽  
Wide Range ◽  
Protein Components

The proteins with the BTB domain play an important role in the processes of activation and repression of transcription. Interestingly, BTB-containing proteins are widely distributed only among higher eukaryotes. Many BTB-containing proteins are transcriptional factors involved in a wide range of developmental processes. One of the key regulators of early development is the BTB-containing protein Ttk (tramtrack), which is able to interact with the Drosophila nucleosome remodeling and histone deacetylation (dNuRD) complex. Ttk69 directly interacts with two protein components of the dNuRD complex, dMi-2 and MEP1. It can be assumed that Ttk69 represses some target genes by remodeling chromatin structure through the recruitment of the dNuRD complex. However, it is still unknown what provides for specific recruitment of Ttk to chromatin in the process of negative/positive regulation of a target gene expression. Although Ttk69 has DNA-binding activity, no extended specific motif has been identified. The purpose of this study was to find proteins that can participate in the recruitment of Ttk to regulatory elements. To identify Ttk partner proteins, screening in the yeast two-hybrid system was performed against a collection of proteins with clusters of C2H2 domains, which bind effectively and specifically to sites on chromatin. As a results, the CG10321 and CG1792 proteins were identified as potential DNA-binding partners of Ttk. We suppose that the CG10321 and CG1792 proteins provide specificity for the recruitment of Ttk and, as a result, of the NuRD-complex to the genome regulatory elements. We found that the Ttk protein is able to interact with the MEP1 and ZnF proteins at once.

scholarly journals Recruitment of the Histone Methyltransferase SUV39H1 and Its Role in the Oncogenic Properties of the Leukemia-Associated PML-Retinoic Acid Receptor Fusion Protein

2006 ◽  
Vol 26 (4) ◽  
pp. 1288-1296 ◽  
Author(s):  
Roberta Carbone ◽  
Oronza A. Botrugno ◽  
Simona Ronzoni ◽  
Alessandra Insinga ◽  
Luciano Di Croce ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Fusion Protein ◽  
Fusion Proteins ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Histone Methyltransferase ◽  
Dna Methyltransferases ◽  
Histone Deacetylation ◽  
Leukemic Cells ◽  
Acid Receptor

ABSTRACT Leukemia-associated fusion proteins establish aberrant transcriptional programs, which result in the block of hematopoietic differentiation, a prominent feature of the leukemic phenotype. The dissection of the mechanisms of deregulated transcription by leukemia fusion proteins is therefore critical for the design of tailored antileukemic strategies, aimed at reestablishing the differentiation program of leukemic cells. The acute promyelocytic leukemia (APL)-associated fusion protein PML-retinoic acid receptor (RAR) behaves as an aberrant transcriptional repressor, due to its ability to induce chromatin modifications (histone deacetylation and DNA methylation) and silencing of PML-RAR target genes. Here, we indicate that the ultimate result of PML-RAR action is to impose a heterochromatin-like structure on its target genes, thereby establishing a permanent transcriptional silencing. This effect is mediated by the previously described association of PML-RAR with chromatin-modifying enzymes (histone deacetylases and DNA methyltransferases) and by recruitment of the histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3.

scholarly journals O-GlcNAc regulates MTA1 transcriptional activity during breast cancer cells genotoxic adaptation

2021 ◽  
Author(s):  
Xueqin Xie ◽  
Qiutong Wu ◽  
Keren Zhang ◽  
Yimin Liu ◽  
Nana Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcriptional Regulation ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Genotoxic Stress ◽  
Histone Deacetylation ◽  
Nurd Complex ◽  
Nucleosome Remodeling

AbstractChromatin modifier metastasis-associated protein 1 (MTA1), closely correlated with the development and progression in breast cancer, has a vital role in multiple cellular processes, including gene expression and cell homeostasis. Although MTA1 is a stress-responsive gene, its role in genotoxic adaptation remains unexplored. The current study sought to investigate the role of MTA1 and its O-GlcNAc modification in breast cancer cells genotoxic adaptation by using quantitative proteomics, ChIP-seq, transcriptome analysis, loss-and gain-of-functions experiments. We demonstrate that O-GlcNAc modification promotes MTA1 to interact with chromatin and regulates target gene expression, contributing to breast cancer cell genotoxic adaptation. MTA1 is modified with O-GlcNAc residues at serine 237/241/246 in adriamycin adaptive breast cancer cells and that modification improves the genome-wide interactions of MTA1 with gene promotor regions by enhancing its association with nucleosome remodeling and histone deacetylation (NuRD) complex. Further, O-GlcNAc-modulated MTA1 chromatin-binding influences the specific transcriptional regulation of genes involved in the adaptation of breast cancer cells to genotoxic stress. Our findings reveal a previously unrecognized role of O-GlcNAc MTA1 in transcriptional regulation and suggest that O-GlcNAc modification is a promising therapeutic target to overcome chemoresistance in breast cancers.

scholarly journals STEM-13. FUNCTIONAL CHARACTERIZATION OF THE ZFHX4-CHD4 INTERACTION IN GLIOBLASTOMA CANCER STEM CELLS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii199-ii199
Author(s):  
Luciano Galdieri ◽  
Mitchell Grinwald ◽  
Zibi Gugala ◽  
Edward Oates ◽  
Milan Chheda
Keyword(s):  
Amino Acids ◽  
Stem Cells ◽  
Zinc Finger ◽  
Functional Characterization ◽  
Histone Deacetylation ◽  
Structural Basis ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
New Treatments ◽  
And Function

Abstract Glioblastoma stem cells (GSCs) they may be one reason for inevitable recurrence of GBM. We previously discovered that Zinc Finger Homeobox 4 (ZFHX4), a 450kD transcription factor, is required to maintain the GSC state. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex, which activates or represses gene expression via two distinct functions - histone deacetylation and ATP-dependent chromatin remodeling. CHD4 suppression phenocopies ZFHX4 suppression. The precise nature and function of the ZFHX4 interaction with CHD4 is not understood. Here we report that the ZFHX4-CHD4 interaction requires a single zinc-finger domain. An incremental truncation screen revealed that ZFHX4 amino acids 1838 to 2387, which contains zinc fingers 14 and 15, are required to bind CHD4. Disrupting the zinc coordination of zinc finger 14 impaired the ZFHX4-CHD4 interaction. Moreover, by overexpressing ZFHX4 amino acids 1838 to 2487, we decreased CHD4 recruitment to transcription regulatory regions of the stem cell genes SOX2 and SOX9, decreased transcription, and reduced clonogenic self-renewal. These results may provide the structural basis for new treatments to target GSCs and prevent recurrence in this devastating disease.

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

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.

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

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.

scholarly journals Reversing Post-Infectious Epigenetic-Mediated Immune Suppression

2021 ◽  
Vol 12 ◽  
Author(s):  
Abhimanyu ◽  
Carlos O. Ontiveros ◽  
Rosa S. Guerra-Resendez ◽  
Tomoki Nishiguchi ◽  
Malik Ladki ◽  
...  
Keyword(s):  
Animal Models ◽  
Immune Suppression ◽  
Wound Repair ◽  
Host Immunity ◽  
Nurd Complex ◽  
Chronic Infections ◽  
Activated T Cells ◽  
Nucleosome Remodeling ◽  
Epigenetic Marks

The immune response must balance the pro-inflammatory, cell-mediated cytotoxicity with the anti-inflammatory and wound repair response. Epigenetic mechanisms mediate this balance and limit host immunity from inducing exuberant collateral damage to host tissue after severe and chronic infections. However, following treatment for these infections, including sepsis, pneumonia, hepatitis B, hepatitis C, HIV, tuberculosis (TB) or schistosomiasis, detrimental epigenetic scars persist, and result in long-lasting immune suppression. This is hypothesized to be one of the contributing mechanisms explaining why survivors of infection have increased all-cause mortality and increased rates of unrelated secondary infections. The mechanisms that induce epigenetic-mediated immune suppression have been demonstrated in-vitro and in animal models. Modulation of the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR), nuclear factor of activated T cells (NFAT) or nuclear receptor (NR4A) pathways is able to block or reverse the development of detrimental epigenetic scars. Similarly, drugs that directly modify epigenetic enzymes, such as those that inhibit histone deacetylases (HDAC) inhibitors, DNA hypomethylating agents or modifiers of the Nucleosome Remodeling and DNA methylation (NuRD) complex or Polycomb Repressive Complex (PRC) have demonstrated capacity to restore host immunity in the setting of cancer-, LCMV- or murine sepsis-induced epigenetic-mediated immune suppression. A third clinically feasible strategy for reversing detrimental epigenetic scars includes bioengineering approaches to either directly reverse the detrimental epigenetic marks or to modify the epigenetic enzymes or transcription factors that induce detrimental epigenetic scars. Each of these approaches, alone or in combination, have ablated or reversed detrimental epigenetic marks in in-vitro or in animal models; translational studies are now required to evaluate clinical applicability.

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

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anne Helness ◽  
Jennifer Fraszczak ◽  
Charles Joly-Beauparlant ◽  
Halil Bagci ◽  
Christian Trahan ◽  
...  
Keyword(s):  
Dna Binding ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Myeloid Differentiation ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
Chromatin Remodeling Complexes ◽  
Active Transcription ◽  
Neutrophil Differentiation

AbstractGrowth factor indepdendent 1 (GFI1) is a SNAG-domain, DNA binding transcriptional repressor which controls myeloid differentiation through molecular mechanisms and co-factors that still remain to be clearly identified. Here we show that GFI1 associates with the chromodomain helicase DNA binding protein 4 (CHD4) and other components of the Nucleosome remodeling and deacetylase (NuRD) complex. In granulo-monocytic precursors, GFI1, CHD4 or GFI1/CHD4 complexes occupy sites enriched for histone marks associated with active transcription suggesting that GFI1 recruits the NuRD complex to target genes regulated by active or bivalent promoters and enhancers. GFI1 and GFI1/CHD4 complexes occupy promoters that are either enriched for IRF1 or SPI1 consensus binding sites, respectively. During neutrophil differentiation, chromatin closure and depletion of H3K4me2 occurs at different degrees depending on whether GFI1, CHD4 or both are present, indicating that GFI1 is more efficient in depleting of H3K4me2 and -me1 marks when associated with CHD4. Our data suggest that GFI1/CHD4 complexes regulate histone modifications differentially to enable regulation of target genes affecting immune response, nucleosome organization or cellular metabolic processes and that both the target gene specificity and the activity of GFI1 during myeloid differentiation depends on the presence of chromatin remodeling complexes.

Role of C. elegans lin-40 MTA in vulval fate specification and morphogenesis

Development ◽  
2001 ◽  
Vol 128 (23) ◽  
pp. 4911-4921 ◽  
Author(s):  
Zhe Chen ◽  
Min Han
Keyword(s):  
Cell Fusion ◽  
Histone Deacetylation ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
Fate Specification ◽  
C Elegans ◽  
Cellular Processes ◽  
Inhibitory Function ◽  
And Migration

Vulval differentiation in Caenorhabditis elegans involves several fundamental cellular events, including cell fusion, division and migration. We have characterized the role of the lin-40 (also known as egr-1) gene in these cellular processes. LIN-40 is homologous to the metastasis-associated factor 1 (MTA1) in mammals, which has been identified as a component of the nucleosome remodeling and histone deacetylation (NuRD) complex that functions as a transcriptional co-repressor. We show here that lin-40 negatively regulates vulval fate specification at least partly by promoting cell fusion between the vulval precursor cells and the hypodermal syncytium at an early larval stage. This inhibitory function of lin-40 might be carried out by downregulating lin-39 Hox expression. We also show that lin-40 is specifically required for cell divisions along the transverse orientation during vulval morphogenesis.

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