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1.
Sci Immunol ; 7(72): eabn5917, 2022 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-35687698

RESUMO

Although BTB-zinc finger (BTB-ZF) transcription factors control the differentiation of multiple hematopoietic and immune lineages, how they function is poorly understood. The BTB-ZF factor Thpok controls intrathymic CD4+ T cell development and the expression of most CD4+ and CD8+ lineage genes. Here, we identify the nucleosome remodeling and deacetylase (NuRD) complex as a critical Thpok cofactor. Using mass spectrometry and coimmunoprecipitation in primary T cells, we show that Thpok binds NuRD components independently of DNA association. We locate three amino acid residues within the Thpok BTB domain that are required for both NuRD binding and Thpok functions. Conversely, a chimeric protein merging the NuRD component Mta2 to a BTB-less version of Thpok supports CD4+ T cell development, indicating that NuRD recruitment recapitulates the functions of the Thpok BTB domain. We found that NuRD mediates Thpok repression of CD8+ lineage genes, including the transcription factor Runx3, but is dispensable for Cd4 expression. We show that these functions cannot be performed by the BTB domain of the Thpok-related factor Bcl6, which fails to bind NuRD. Thus, cofactor binding critically contributes to the functional specificity of BTB-ZF factors, which control the differentiation of most hematopoietic subsets.


Assuntos
Linfócitos T CD4-Positivos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Diferenciação Celular , Linhagem da Célula , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Fatores de Transcrição
2.
Development ; 149(11)2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35695185

RESUMO

In the developing subpallium, the fate decision between neurons and glia is driven by expression of Dlx1/2 or Olig1/2, respectively, two sets of transcription factors with a mutually repressive relationship. The mechanism by which Dlx1/2 repress progenitor and oligodendrocyte fate, while promoting transcription of genes needed for differentiation, is not fully understood. We identified a motif within DLX1 that binds RBBP4, a NuRD complex subunit. ChIP-seq studies of genomic occupancy of DLX1 and six different members of the NuRD complex show that DLX1 and NuRD colocalize to putative regulatory elements enriched near other transcription factor genes. Loss of Dlx1/2 leads to dysregulation of genome accessibility at putative regulatory elements near genes repressed by Dlx1/2, including Olig2. Consequently, heterozygosity of Dlx1/2 and Rbbp4 leads to an increase in the production of OLIG2+ cells. These findings highlight the importance of the interplay between transcription factors and chromatin remodelers in regulating cell-fate decisions.


Assuntos
Proteínas de Homeodomínio , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Diferenciação Celular/genética , Genes Homeobox , Proteínas de Homeodomínio/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
3.
Immun Inflamm Dis ; 10(7): e644, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35759243

RESUMO

Chromodomain helicase DNA binding protein 4 (CHD4) is an ATPase subunit of the nucleosome remodeling and deacetylation complex. It has been implicated in gene transcription, DNA damage repair, maintenance of genome stability, and chromatin assembly. Meanwhile, it is highly related to cell cycle progression and the proceeding of malignancy. Most of the previous studies were focused on the function of CHD4 with tumor cells, cancer stem cells, and cancer cells multidrug resistance. Recently, some researchers have explored the CHD4 functions on the development and differentiation of adaptive immune cells, such as T and B lymphocytes. In this review, we will discuss details of CHD4 in lymphocyte differentiation and development, as well as the critical role of CHD4 in the pathogenesis of the autoimmune disease.


Assuntos
Doenças Autoimunes , Montagem e Desmontagem da Cromatina , Linfócitos B/metabolismo , Diferenciação Celular , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Nucleossomos , Linfócitos T
4.
Cell Rep ; 39(6): 110788, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35545047

RESUMO

Kaposi sarcoma-associated herpesvirus (KSHV) establishes a latent infection in the cell nucleus, but where KSHV episomal genomes are tethered and the mechanisms underlying KSHV lytic reactivation are unclear. Here, we study the nuclear microenvironment of KSHV episomes and show that the KSHV latency-lytic replication switch is regulated via viral long non-coding (lnc)RNA-CHD4 (chromodomain helicase DNA binding protein 4) interaction. KSHV episomes localize with CHD4 and ADNP proteins, components of the cellular ChAHP complex. The CHD4 and ADNP proteins occupy the 5'-region of the highly inducible lncRNAs and terminal repeats of the KSHV genome together with latency-associated nuclear antigen (LANA). Viral lncRNA binding competes with CHD4 DNA binding, and KSHV reactivation sequesters CHD4 from the KSHV genome, which is also accompanied by detachment of KSHV episomes from host chromosome docking sites. We propose a model in which robust KSHV lncRNA expression determines the latency-lytic decision by regulating LANA/CHD4 binding to KSHV episomes.


Assuntos
Herpesvirus Humano 8 , RNA Longo não Codificante , Sarcoma de Kaposi , Antígenos Virais/genética , Antígenos Virais/metabolismo , Cromossomos/metabolismo , Herpesvirus Humano 8/genética , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Plasmídeos , RNA Longo não Codificante/genética , Microambiente Tumoral , Latência Viral/genética
5.
J Mol Endocrinol ; 69(2): 329-341, 2022 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-35521759

RESUMO

Type 2 diabetes (T2D) is associated with loss of transcription factors (TFs) from a subset of failing ß-cells. Among these TFs is Pdx1, which controls the expression of numerous genes involved in maintaining ß-cell function and identity. Pdx1 activity is modulated by transcriptional coregulators and has recently been shown, through an unbiased screen, to interact with the Chd4 ATPase subunit of the nucleosome remodeling and deacetylase complex. Chd4 contributes to the maintenance of cellular identity and functional status of numerous different cell types. Here, we demonstrated that Pdx1 dynamically interacts with Chd4 under physiological and stimulatory conditions within islet ß-cells and established a fundamental role for Chd4 in regulating insulin secretion and modulating numerous Pdx1-bound genes in vitro, including the MafA TF, where we discovered Chd4 is bound to the MafA region 3 enhancer. Furthermore, we found that Pdx1:Chd4 interactions are significantly compromised in islet ß-cells under metabolically induced stress in vivo and in human donor tissues with T2D. Our findings establish a fundamental role for Chd4 in regulating insulin secretion and modulating Pdx1-bound genes in vitro, and disruption of Pdx1:Chd4 interactions coincides with ß-cell dysfunction associated with T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
6.
Epigenetics Chromatin ; 15(1): 16, 2022 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-35568926

RESUMO

Testis development and sustained germ cell production in adults rely on the establishment and maintenance of spermatogonia stem cells and their proper differentiation into spermatocytes. Chromatin remodeling complexes regulate critical processes during gamete development by restricting or promoting accessibility of DNA repair and gene expression machineries to the chromatin. Here, we investigated the role of Chd4 and Chd3 catalytic subunits of the NURD complex during spermatogenesis. Germ cell-specific deletion of chd4 early in gametogenesis, but not chd3, resulted in arrested early gamete development due to failed cell survival of neonate undifferentiated spermatogonia stem cell population. Candidate assessment revealed that Chd4 controls expression of dmrt1 and its downstream target plzf, both described as prominent regulators of spermatogonia stem cell maintenance. Our results show the requirement of Chd4 in mammalian gametogenesis pointing to functions in gene expression early in the process.


Assuntos
DNA Helicases/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Espermatogônias , Animais , Diferenciação Celular , Gônadas , Masculino , Mamíferos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Camundongos , Fatores de Transcrição/genética
7.
Arch Toxicol ; 96(6): 1739-1749, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35362730

RESUMO

Epigenetic complex NuRD (nucleosome remodeling and deacetylase) engages in a range of basic cellular processes, including chromatin modification. Changes in the activity of NuRD complex can influence gastric cancer progression. Multivariate logistic regression analyses were used to estimate the association between single-nucleotide polymorphisms (SNPs) and gastric cancer risk. Expression quantitative trait loci (eQTL) analysis was used to analyze the relationship between the genotypes and gene expression levels using data from the genotype tissue expression project (GTEx). Gene expression was calculated using databases from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO). Kaplan-Meier plotter was used to evaluate the association between gene expression and survival. SNP rs11064275 T allele in CHD4, rs892022 A allele and rs2033481 A allele in GATAD2A were found to contribute to the decreased risk of gastric cancer. The increase in the number of favorable alleles of these three SNPs was associated with a lower risk of gastric cancer. rs2033481 and rs892022 were substantially correlated with GATAD2A mRNA expression levels. Meanwhile, we detected that the CHD4 and GATAD2A mRNA expression was increased in gastric cancer tissues compared with the adjacent normal tissues. Furthermore, we found that patients with higher CHD4 or GATAD2A mRNA expression level had more advantageous overall survival. Our findings indicated that genetic variants in NuRD complex subunits encoding genes may be promising predictors of gastric cancer risk.


Assuntos
Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Neoplasias Gástricas , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Nucleossomos/genética , RNA Mensageiro , Neoplasias Gástricas/genética
8.
Genes Dev ; 36(7-8): 468-482, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35450884

RESUMO

The nucleosome remodeling and deacetylase (NuRD) complex is one of the central chromatin remodeling complexes that mediates gene repression. NuRD is essential for numerous developmental events, including heart development. Clinical and genetic studies have provided direct evidence for the role of chromodomain helicase DNA-binding protein 4 (CHD4), the catalytic component of NuRD, in congenital heart disease (CHD), including atrial and ventricular septal defects. Furthermore, it has been demonstrated that CHD4 is essential for mammalian cardiomyocyte formation and function. A key unresolved question is how CHD4/NuRD is localized to specific cardiac target genes, as neither CHD4 nor NuRD can directly bind DNA. Here, we coupled a bioinformatics-based approach with mass spectrometry analyses to demonstrate that CHD4 interacts with the core cardiac transcription factors GATA4, NKX2-5, and TBX5 during embryonic heart development. Using transcriptomics and genome-wide occupancy data, we characterized the genomic landscape of GATA4, NKX2-5, and TBX5 repression and defined the direct cardiac gene targets of the GATA4-CHD4, NKX2-5-CHD4, and TBX5-CHD4 complexes. These data were used to identify putative cis-regulatory elements controlled by these complexes. We genetically interrogated two of these silencers in vivo: Acta1 and Myh11 We show that deletion of these silencers leads to inappropriate skeletal and smooth muscle gene misexpression, respectively, in the embryonic heart. These results delineate how CHD4/NuRD is localized to specific cardiac loci and explicates how mutations in the broadly expressed CHD4 protein lead to cardiac-specific disease states.


Assuntos
DNA Helicases , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Animais , DNA Helicases/metabolismo , Genes Homeobox , Mamíferos/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Miócitos Cardíacos/metabolismo , Nucleossomos , Fatores de Transcrição/genética
9.
Genetics ; 221(1)2022 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-35323946

RESUMO

During proteotoxic stress, a pathway known as the heat shock response is induced to maintain protein-folding homeostasis or proteostasis. Previously, we identified the Caenorhabditis elegans GATAD2 ortholog, dcp-66, as a novel regulator of the heat shock response. Here, we extend these findings to show that dcp-66 positively regulates the heat shock response at the cellular, molecular, and organismal levels. As GATAD2 is a subunit of the nucleosome remodeling and deacetylase chromatin remodeling complex, we examined other nucleosome remodeling and deacetylase subunits and found that the let-418 (CHD4) nucleosome repositioning core also regulates the heat shock response. However, let-418 acts as a negative regulator of the heat shock response, in contrast to positive regulation by dcp-66. The divergent effects of these two nucleosome remodeling and deacetylase subunits extend to the regulation of other stress responses including oxidative, genotoxic, and endoplasmic reticulum stress. Furthermore, a transcriptomic approach reveals additional divergently regulated pathways, including innate immunity and embryogenesis. Taken together, this work establishes new insights into the role of nucleosome remodeling and deacetylase subunits in organismal physiology. We incorporate these findings into a molecular model whereby different mechanisms of recruitment to promoters can result in the divergent effects of nucleosome remodeling and deacetylase subunits.


Assuntos
Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Nucleossomos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Montagem e Desmontagem da Cromatina , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Nucleossomos/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
10.
Genet Med ; 24(6): 1283-1296, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35346573

RESUMO

PURPOSE: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. METHODS: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. RESULTS: Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. CONCLUSION: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease.


Assuntos
DNA Helicases , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Transtornos do Neurodesenvolvimento , DNA Helicases/genética , Heterozigoto , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Síndrome
11.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35105803

RESUMO

BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2 As such, BRD4 inhibitors are being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here, we report that BRD4 unexpectedly interacts with the LSD1/NuRD complex and colocalizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small-molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Neoplasias/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteínas de Ciclo Celular/genética , Feminino , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Células MCF-7 , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética
12.
FEBS J ; 289(1): 199-214, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34231305

RESUMO

The 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 remodelling module of the nucleosome remodelling and deacetylase (NuRD) complex. To date, mechanisms by which the MGCC module acquires paralogue-specific function and specificity have not been addressed. Understanding the protein-protein interaction (PPI) network of the MGCC subunits is essential for defining underlying mechanisms of gene regulation. 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 remodelling activity into both 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.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Mapas de Interação de Proteínas/genética , Proteoma/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/ultraestrutura , Complexos Multiproteicos/genética , Nucleossomos/genética , Nucleossomos/ultraestrutura , Proteínas Repressoras/genética , Proteínas Supressoras de Tumor/genética
13.
Immunol Rev ; 305(1): 29-42, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34927255

RESUMO

B lymphocytes develop from uncommitted precursors into immunoglobulin (antibody)-producing B cells, a major arm of adaptive immunity. Progression of early progenitors to antibody-expressing cells in the bone marrow is orchestrated by the temporal regulation of different gene programs at discrete developmental stages. A major question concerns how B cells control the accessibility of these genes to transcription factors. Research has implicated nucleosome remodeling ATPases as mediators of chromatin accessibility. Here, we describe studies of chromodomain helicase DNA-binding 4 (CHD4; also known as Mi-2ß) in early B cell development. CHD4 comprises multiple domains that function in nucleosome mobilization and histone binding. CHD4 is a key component of Nucleosome Remodeling and Deacetylase, or NuRD (Mi-2) complexes, which assemble with other proteins that mediate transcriptional repression. We review data demonstrating that CHD4 is necessary for B lineage identity: early B lineage progression, proliferation in response to interleukin-7, responses to DNA damage, and cell survival in vivo. CHD4-NuRD is also required for the Ig heavy-chain repertoire by promoting utilization of distal variable (VH ) gene segments in V(D)J recombination. In conclusion, the regulation of chromatin accessibility by CHD4 is essential for production of antibodies by B cells, which in turn mediate humoral immune responses to pathogens and disease.


Assuntos
Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Recombinação V(D)J , Linfócitos B/metabolismo , DNA , DNA Helicases/genética , DNA Helicases/metabolismo , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo
14.
Genes Cells ; 27(1): 61-71, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34897913

RESUMO

The CHD (chromodomain helicase DNA binding protein) family consists of nine chromatin remodeling factors that alter chromatin structure in an ATP-dependent manner. CHD4 contributes to the regulation of various cellular activities and processes including development through interaction with multiple proteins including formation of the NuRD (nucleosome remodeling and deacetylase activity) complex. Functions of CHD4 that appear not to be mediated by the NuRD complex or other known interactors have also been identified, however, suggesting the existence of unrecognized proteins that also associate with CHD4. We here generated HeLa-S3 and HEK293T cells with a knock-in allele for FLAG epitope-tagged CHD4 and used these cells to identify proteins that bind to CHD4 with the use of immunoprecipitation followed by liquid chromatography and tandem mass spectrometry. LCORL (ligand-dependent nuclear receptor corepressor like) and NOL4L (nucleolar protein 4 like) were reproducibly identified as novel CHD4 interactors. Furthermore, RNA-sequencing analysis of HEK293T cells depleted of CHD4, LCORL, or NOL4L revealed consistent up-regulation of genes related to the Notch signaling pathway. Our results thus suggest that both LCORL and NOL4L may cooperate with CHD4 to suppress the Notch pathway in mammalian cells.


Assuntos
Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Nucleossomos , Animais , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Células HEK293 , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Proteínas
15.
Commun Biol ; 4(1): 1356, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34857890

RESUMO

Growth 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.


Assuntos
Cromatina/metabolismo , Proteínas de Ligação a DNA/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Células Progenitoras Mieloides/metabolismo , Fatores de Transcrição/genética , Transcrição Genética , Animais , Proteínas de Ligação a DNA/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Camundongos , Fatores de Transcrição/metabolismo
16.
Mol Biol Cell ; 32(21): ar23, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34495684

RESUMO

Scribble (Scrib), Discs-large (Dlg), and Lethal giant larvae (Lgl) are basolateral regulators of epithelial polarity and tumor suppressors whose molecular mechanisms of action remain unclear. We used proximity biotinylation to identify proteins localized near Dlg in the Drosophila wing imaginal disc epithelium. In addition to expected membrane- and cytoskeleton-associated protein classes, nuclear proteins were prevalent in the resulting mass spectrometry dataset, including all four members of the nucleosome remodeling factor (NURF) chromatin remodeling complex. Subcellular fractionation demonstrated a nuclear pool of Dlg and proximity ligation confirmed its position near the NURF complex. Genetic analysis showed that NURF activity is also required for the overgrowth of dlg tumors, and this growth suppression correlated with a reduction in Hippo pathway gene expression. Together, these data suggest a nuclear role for Dlg in regulating chromatin and transcription through a more direct mechanism than previously thought.


Assuntos
Proteínas de Drosophila/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Polaridade Celular/genética , Proteínas do Citoesqueleto/metabolismo , Proteínas de Drosophila/fisiologia , Drosophila melanogaster , Células Epiteliais/metabolismo , Epitélio , Discos Imaginais/metabolismo , Proteínas de Membrana/metabolismo , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Proteínas Nucleares/metabolismo , Proteína Quinase C/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/fisiologia
17.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(9): 965-968, 2021.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34535214

RESUMO

A one-year and two-month old girl indicated large head circumference, widely spaced eyes, narrow palpebral fissures, strabismus on the right eye, broad and low nasal bridge and low-set ears. She had knee over extension and foot eversion on both sides while standing with help. She also had hypotonia and was not able to stand or walk independently. She can say "ma ma" unconsciously. In the neuropsychological developmental assessment, delayed development was shown on gross motor function, fine movement, adaptive capacity, speech and social behavior function. A de novo heterozygous mutation, c.3872G>A(p.G1291D), likely pathogenic, was detected in the CHD3 gene via the next generation sequencing. Snijders Blok-Campeau syndrome was confirmed. It is an extremely rare disease with only 60 cases reported globally. This case expands the CHD3 gene mutation sites and suggests that rare diseases need to be considered and genetic tests should be performed in children with intellectual developmental delay and abnormal facial features, so as to help early diagnosis. Citation.


Assuntos
DNA Helicases/genética , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/genética , Hipotonia Muscular , Comportamento Social , Feminino , Heterozigoto , Humanos , Lactente , Hipotonia Muscular/genética , Mutação
18.
Stem Cell Reports ; 16(9): 2089-2098, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34450038

RESUMO

Regeneration of skeletal muscle requires resident stem cells called satellite cells. Here, we report that the chromatin remodeler CHD4, a member of the nucleosome remodeling and deacetylase (NuRD) repressive complex, is essential for the expansion and regenerative functions of satellite cells. We show that conditional deletion of the Chd4 gene in satellite cells results in failure to regenerate muscle after injury. This defect is principally associated with increased stem cell plasticity and lineage infidelity during the expansion of satellite cells, caused by de-repression of non-muscle-cell lineage genes in the absence of Chd4. Thus, CHD4 ensures that a transcriptional program that safeguards satellite cell identity during muscle regeneration is maintained. Given the therapeutic potential of muscle stem cells in diverse neuromuscular pathologies, CHD4 constitutes an attractive target for satellite cell-based therapies.


Assuntos
Diferenciação Celular/genética , Linhagem da Célula/genética , DNA Helicases/genética , Músculo Esquelético/fisiologia , Regeneração , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Biologia Computacional , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo , Camundongos , Modelos Biológicos , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/metabolismo
19.
BMC Biol ; 19(1): 148, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34340707

RESUMO

BACKGROUND: Methylation of cytosines in DNA (5mC methylation) is a major epigenetic modification that modulates gene expression and constitutes the basis for mechanisms regulating multiple aspects of embryonic development and cell reprogramming in vertebrates. In mammals, 5mC methylation of promoter regions is linked to transcriptional repression. Transcription regulation by 5mC methylation notably involves the nucleosome remodeling and deacetylase complex (NuRD complex) which bridges DNA methylation and histone modifications. However, less is known about regulatory mechanisms involving 5mC methylation and their function in non-vertebrate animals. In this paper, we study 5mC methylation in the marine annelid worm Platynereis dumerilii, an emerging evolutionary and developmental biology model capable of regenerating the posterior part of its body post-amputation. RESULTS: Using in silico and experimental approaches, we show that P. dumerilii displays a high level of DNA methylation comparable to that of mammalian somatic cells. 5mC methylation in P. dumerilii is dynamic along the life cycle of the animal and markedly decreases at the transition between larval to post-larval stages. We identify a full repertoire of mainly single-copy genes encoding the machinery associated with 5mC methylation or members of the NuRD complex in P. dumerilii and show that this repertoire is close to the one inferred for the last common ancestor of bilaterians. These genes are dynamically expressed during P. dumerilii development and regeneration. Treatment with the DNA hypomethylating agent Decitabine impairs P. dumerilii larval development and regeneration and has long-term effects on post-regenerative growth. CONCLUSIONS: Our data reveal high levels of 5mC methylation in the annelid P. dumerilii, highlighting that this feature is not specific to vertebrates in the bilaterian clade. Analysis of DNA methylation levels and machinery gene expression during development and regeneration, as well as the use of a chemical inhibitor of DNA methylation, suggest an involvement of 5mC methylation in P. dumerilii development and regeneration. We also present data indicating that P. dumerilii constitutes a promising model to study biological roles and mechanisms of DNA methylation in non-vertebrate bilaterians and to provide new knowledge about evolution of the functions of this key epigenetic modification in bilaterian animals.


Assuntos
Metilação de DNA , Poliquetos , Animais , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase , Poliquetos/genética , Vertebrados
20.
J Dermatol Sci ; 103(2): 66-72, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34238638

RESUMO

The skin, which is constantly exposed to a wide variety of environmental insults, maintains its integrity by rapidly responding to external signals. In the epidermis, most genes are set in transcriptionally poised conditions to prepare for the prompt induction of stress responding genes. Local chromatin dynamics, supported by an interplay between epigenetic regulators and transcription factors, underlies transcriptional responses upon stress exposure. This review summarizes the epigenetic mechanism regulating gene expression and discusses how stress signaling provokes chromatin reprogramming in the epidermis. Epigenetic regulators play a leading role in chromatin remodeling during stress adaptation, and the timely release and restoration of these factors are indispensable for an appropriate skin repair. Evidence for the epigenetic regulation of physiological responses in the skin is accumulating. The epigenetic environment under continuous stress stimuli may lead to the acquisition of stress tolerance, but at the same time, may also induce pathological hypersensitivity. This review describes the current understanding of epigenetics and provides the potential of epigenetic regulation in skin disease development.


Assuntos
Adaptação Fisiológica , Cromatina/metabolismo , Epiderme/metabolismo , Epigênese Genética , Estresse Fisiológico , Animais , Montagem e Desmontagem da Cromatina , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Complexo Mi-2 de Remodelação de Nucleossomo e Desacetilase/metabolismo
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