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.

Structural and functional characterization of the RBBP4–ZNF827 interaction and its role in NuRD recruitment to telomeres

2018 ◽  
Vol 475 (16) ◽  
pp. 2667-2679 ◽  
Author(s):  
Sile F. Yang ◽  
Ai-ai Sun ◽  
Yunyu Shi ◽  
Fudong Li ◽  
Hilda A. Pickett
Keyword(s):  
Amino Acids ◽  
Electrostatic Interactions ◽  
Zinc Finger Protein ◽  
Functional Characterization ◽  
Vital Role ◽  
Telomere Maintenance ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
Alternative Lengthening

The nucleosome remodeling and histone deacetylase (NuRD) complex is an essential multi-subunit protein complex that regulates higher-order chromatin structure. Cancers that use the alternative lengthening of telomere (ALT) pathway of telomere maintenance recruit NuRD to their telomeres. This interaction is mediated by the N-terminal domain of the zinc-finger protein ZNF827. NuRD–ZNF827 plays a vital role in the ALT pathway by creating a molecular platform for recombination-mediated repair. Disruption of NuRD binding results in loss of ALT cell viability. Here, we present the crystal structure of the NuRD subunit RBBP4 bound to the N-terminal 14 amino acids of ZNF827. RBBP4 forms a negatively charged channel that binds to ZNF827 through a network of electrostatic interactions. We identify the precise amino acids in RBBP4 required for this interaction and demonstrate that disruption of these residues prevents RBBP4 binding to both ZNF827 and telomeres, but is insufficient to decrease ALT activity. These data provide insights into the structural and functional determinants of NuRD activity at ALT telomeres.

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 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 BRG1 GovernsNanogTranscription in Early Mouse Embryos and Embryonic Stem Cells via Antagonism of Histone H3 Lysine 9/14 Acetylation

2015 ◽  
Vol 35 (24) ◽  
pp. 4158-4169 ◽  
Author(s):  
Timothy S. Carey ◽  
Zubing Cao ◽  
Inchul Choi ◽  
Avishek Ganguly ◽  
Catherine A. Wilson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Histone H3 ◽  
Embryonic Stem ◽  
Histone Deacetylation ◽  
Preimplantation Embryos ◽  
Nucleosome Remodeling ◽  
Histone Deacetylase 1

During mouse preimplantation development, the generation of the inner cell mass (ICM) and trophoblast lineages comprises upregulation ofNanogexpression in the ICM and its silencing in the trophoblast. However, the underlying epigenetic mechanisms that differentially regulateNanogin the first cell lineages are poorly understood. Here, we report that BRG1 (Brahma-related gene 1) cooperates with histone deacetylase 1 (HDAC1) to regulateNanogexpression. BRG1 depletion in preimplantation embryos andCdx2-inducible embryonic stem cells (ESCs) revealed that BRG1 is necessary forNanogsilencing in the trophoblast lineage. Conversely, in undifferentiated ESCs, loss of BRG1 augmentedNanogexpression. Analysis of histone H3 within theNanogproximal enhancer revealed that H3 lysine 9/14 (H3K9/14) acetylation increased in BRG1-depleted embryos and ESCs. Biochemical studies demonstrated that HDAC1 was present in BRG1-BAF155 complexes and BRG1-HDAC1 interactions were enriched in the trophoblast lineage. HDAC1 inhibition triggered an increase in H3K9/14 acetylation and a corresponding rise inNanogmRNA and protein, phenocopying BRG1 knockdown embryos and ESCs. Lastly, nucleosome-mapping experiments revealed that BRG1 is indispensable for nucleosome remodeling at theNanogenhancer during trophoblast development. In summary, our data suggest that BRG1 governsNanogexpression via a dual mechanism involving histone deacetylation and nucleosome remodeling.

scholarly journals Characterization of Two Distinct Nucleosome Remodeling and Deacetylase (NuRD) Complex Assemblies in Embryonic Stem Cells

2015 ◽  
Vol 15 (3) ◽  
pp. 878-891 ◽  
Author(s):  
Daniel Bode ◽  
Lu Yu ◽  
Peri Tate ◽  
Mercedes Pardo ◽  
Jyoti Choudhary
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Nurd Complex ◽  
Nucleosome Remodeling

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

2010 ◽  
Vol 3 ◽  
pp. PRI.S6329 ◽  
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.

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.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

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