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.

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 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 Identification of key genes and associated pathways in neuroendocrine tumors through bioinformatics analysis and predictions of small drug molecules

2020 ◽  
Author(s):  
Praveenkumar Devarbhavi ◽  
Basavaraj Vastrad ◽  
Anandkumar Tengli ◽  
Chanabasayya Vastrad ◽  
Iranna Kotturshetti
Keyword(s):  
Drug Target ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Regulatory Elements ◽  
Future Research ◽  
High Morbidity ◽  
Hub Genes ◽  
Go Enrichment ◽  
Significant Difference

AbstractNeuroendocrine tumor (NET) is one of malignant cancer and is identified with high morbidity and mortality rates around the world. With indigent clinical outcomes, potential biomarkers for diagnosis, prognosis and drug target are crucial to explore. The aim of this study is to examine the gene expression module of NET and to identify potential diagnostic and prognostic biomarkers as well as to find out new drug target. The differentially expressed genes (DEGs) identified from GSE65286 dataset was used for pathway enrichment analyses and gene ontology (GO) enrichment analyses and protein - protein interaction (PPI) analysis and module analysis. Moreover, miRNAs and transcription factors (TFs) that regulated the up and down regulated genes were predicted. Furthermore, validation of hub genes was performed. Finally, molecular docking studies were performed. DEGs were identified, including 453 down regulated and 459 up regulated genes. Pathway and GO enrichment analysis revealed that DEGs were enriched in sucrose degradation, creatine biosynthesis, anion transport and modulation of chemical synaptic transmission. Important hub genes and target genes were identified through PPI network, modules, target gene - miRNA network and target gene - TF network. Finally, survival analyses, receiver operating characteristic (ROC) curve and RT-PCR validated the significant difference of ATP1A1, LGALS3, LDHA, SYK, VDR, OBSL1, KRT40, WWOX, NINL and PPP2R2B between metastatic NET and normal controls. In conclusion, the DEGs and hub genes with their regulatory elements identified in this study will help us understand the molecular mechanisms underlying NET and provide candidate targets for future research.

Elevation of MicroRNA-126 Levels in Intracranial Aneurysm and Bioinformatic Analysis of Potential Molecular Mechanisms

2021 ◽  
Vol 11 (4) ◽  
pp. 573-579
Author(s):  
Pan Huang ◽  
Min Xu ◽  
Xiao-Ying He
Keyword(s):  
Intracranial Aneurysm ◽  
Peripheral Blood ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Kegg Pathway ◽  
Bioinformatic Analysis ◽  
Control Group ◽  
Potential Target ◽  
Fas Signaling

The study is to investigation of microRNA-126 levels in patients with intracranial aneurysm and bioinformatic analysis of the molecular mechanisms involved. A total of 166 patients with ICA who were hospitalized or examined in our hospital from September 2015 to December 2017 were used as the experimental group (ICA group). This group included 120 patients with unruptured intracranial aneurysm (UICA; UICA group) and 46 patients with ruptured intracranial aneurysm (RICA); RICA group). The UICA group was further subdivided into 42 surgical groups (S group) and 78 nonsurgical groups (NS group). Sixty-three normal people without intracranial aneurysms were selected as the control group. RT-PCR was used to quantitatively detect the relative expression of microRNA- 126 in peripheral blood mononuclear cells at the time of admission and immediately after surgery. The UCSC database was used to analyze the gene locus and homology of microRNA-126. The TargetScan database and CoMeTa database were used to predict the potential target genes of microRNA-126. The DAVID database was used to enrich the function of potential target genes of microRNA-126 (GO enrichment) and KEGG pathway enrichment for analysis. The expression level of microRNA-126 in peripheral blood was significantly higher in the ICA group than in the control group (P <0.01), significantly higher in the RICA group than in the UICA group (P <0.05). Expression was also higher in the NS group than in the S group but the difference was nonsignificant (P >0.05). A total of 15 potential target genes including ITGA6, CRK, PCDH7, and ADAM9 were identified through the target gene prediction software and GO analysis and KEGG pathway analysis showed that the function of the microRNA-126 target gene was mainly focused on protein binding and the FAS signaling pathway. In Conclusion the microRNA-126 is up-regulated in ICA patients and affects ICA by regulating multiple target genes in the FAS signaling pathway.

scholarly journals Differential Contribution of N- and C-Terminal Regions of HIF1α and HIF2α to Their Target Gene Selectivity

2020 ◽  
Vol 21 (24) ◽  
pp. 9401
Author(s):  
Antonio Bouthelier ◽  
Florinda Meléndez-Rodríguez ◽  
Andrés A. Urrutia ◽  
Julián Aragonés
Keyword(s):  
Transcription Factors ◽  
Dna Binding ◽  
Cellular Response ◽  
Target Gene ◽  
Target Genes ◽  
Transactivation Domain ◽  
Transactivation Domains ◽  
Relative Contribution

Cellular response to hypoxia is controlled by the hypoxia-inducible transcription factors HIF1α and HIF2α. Some genes are preferentially induced by HIF1α or HIF2α, as has been explored in some cell models and for particular sets of genes. Here we have extended this analysis to other HIF-dependent genes using in vitro WT8 renal carcinoma cells and in vivo conditional Vhl-deficient mice models. Moreover, we generated chimeric HIF1/2 transcription factors to study the contribution of the HIF1α and HIF2α DNA binding/heterodimerization and transactivation domains to HIF target specificity. We show that the induction of HIF1α-dependent genes in WT8 cells, such as CAIX (CAR9) and BNIP3, requires both halves of HIF, whereas the HIF2α transactivation domain is more relevant for the induction of HIF2 target genes like the amino acid carrier SLC7A5. The HIF selectivity for some genes in WT8 cells is conserved in Vhl-deficient lung and liver tissue, whereas other genes like Glut1 (Slc2a1) behave distinctly in these tissues. Therefore the relative contribution of the DNA binding/heterodimerization and transactivation domains for HIF target selectivity can be different when comparing HIF1α or HIF2α isoforms, and that HIF target gene specificity is conserved in human and mouse cells for some of the genes analyzed.

Copper affects the binding of HIF-1α to the critical motifs of its target genes

Metallomics ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 429-438 ◽  
Author(s):  
Zhijuan Wu ◽  
Wenjing Zhang ◽  
Y. James Kang
Keyword(s):  
Dna Binding ◽  
Target Gene ◽  
Target Genes ◽  
Gene Selection ◽  
Hypoxic Conditions ◽  
Selection Of

Copper regulates the target gene selection of HIF-1α under hypoxic conditions by affecting HIF-1α-DNA binding patterns across the genome.

scholarly journals Enhancer-bound LDB1 regulates a corticotrope promoter-pausing repression program

2015 ◽  
Vol 112 (5) ◽  
pp. 1380-1385 ◽  
Author(s):  
Feng Zhang ◽  
Bogdan Tanasa ◽  
Daria Merkurjev ◽  
Chijen Lin ◽  
Xiaoyuan Song ◽  
...  
Keyword(s):  
Target Gene ◽  
Target Genes ◽  
Binding Protein ◽  
Homeodomain Protein ◽  
Gene Promoters ◽  
Cell Type ◽  
Lim Domain ◽  
Transcriptional Initiation ◽  
Nucleosome Remodeling ◽  
Enhancer Binding Protein

Substantial evidence supports the hypothesis that enhancers are critical regulators of cell-type determination, orchestrating both positive and negative transcriptional programs; however, the basic mechanisms by which enhancers orchestrate interactions with cognate promoters during activation and repression events remain incompletely understood. Here we report the required actions of LIM domain-binding protein 1 (LDB1)/cofactor of LIM homeodomain protein 2/nuclear LIM interactor, interacting with the enhancer-binding protein achaete-scute complex homolog 1, to mediate looping to target gene promoters and target gene regulation in corticotrope cells. LDB1-mediated enhancer:promoter looping appears to be required for both activation and repression of these target genes. Although LDB1-dependent activated genes are regulated at the level of transcriptional initiation, the LDB1-dependent repressed transcription units appear to be regulated primarily at the level of promoter pausing, with LDB1 regulating recruitment of metastasis-associated 1 family, member 2, a component of the nucleosome remodeling deacetylase complex, on these negative enhancers, required for the repressive enhancer function. These results indicate that LDB1-dependent looping events can deliver repressive cargo to cognate promoters to mediate promoter pausing events in a pituitary cell type.

scholarly journals Identification of miRNA and Their Regulatory Effects Induced by Total Flavonoids From Dracocephalum moldavica in the Treatment of Vascular Dementia

2021 ◽  
Vol 12 ◽  
Author(s):  
Mimin Liu ◽  
Guangzhi Shan ◽  
Hailun Jiang ◽  
Li Zeng ◽  
Kaiyue Zhao ◽  
...  
Keyword(s):  
Vascular Dementia ◽  
Target Gene ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Bioinformatics Analysis ◽  
Gene Profiling ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Total Flavonoids ◽  
Compound Target

Vascular dementia (VaD) is a general term used to describe difficulties in memory, reasoning, judgment, and planning caused by a reduced blood flow to the brain and consequent brain damage, in which microRNAs (miRNAs) are involved. Dracocephalum moldavica L. (D. moldavica) is traditionally used in the treatment of cardiovascular diseases as well as VaD, but the biomolecular mechanisms underlying its therapeutic effect are obscure. In the present study, the molecular mechanisms involved in the treatment of VaD by the total flavonoids from Dracocephalum moldavica L. (TFDM) were explored by the identification of miRNA profiling using bioinformatics analysis and experimental verification. A total of 2,562 differentially expressed miRNAs (DEMs) and 3,522 differentially expressed genes (DEGs) were obtained from the GSE120584 and GSE122063 datasets, in which the gene functional enrichment and protein-protein interaction network of 93 core targets, originated from the intersection of the top DEM target genes and DEGs, were established for VaD gene profiling. One hundred and eighty-five targets interacting with 42 flavonoids in the TFDM were included in a compound-target network, subsequently found that they overlapped with potential targets for VaD. These 43 targets could be considered in the treatment of VaD by TFDM, and included CaMKII, MAPK, MAPT, PI3K, and KDR, closely associated with the vascular protective effect of TFDM, as well as anti-oxidative, anti-inflammatory, and anti-apoptotic properties. The subsequent analysis of the compound-target gene-miRNA network indicated that eight miRNAs that mediated 43 targets had a close interaction with TFDM, suggesting that the neuroprotective effects were principally due to kaempferol, apigenin, luteolin, and quercetin, which were mostly associated with the miR-3184-3p/ESR1, miR-6762-3p/CDK1, miR-6777-3p/ESRRA, and other related axes. Furthermore, the in vitro oxygen-glucose deprivation (OGD) model demonstrated that the dysregulation of miR-3184-3p and miR-6875-5p found by qRT-PCR was consistent with the changes in the bioinformatics analysis. TFDM and its active compounds involving tilianin, luteolin, and apigenin showed significant effects on the upregulation of miR-3184-3p and downregulation of miR-6875-5p in OGD-injured cells, in line with the improved cell viability. In conclusion, our findings revealed the underlying miRNA-target gene network and potential targets of TFDM in the treatment of VaD.

scholarly journals CHD4-NURD controls spermatogonia survival and differentiation

2019 ◽  
Author(s):  
Rodrigo O. de Castro ◽  
Victor Goitea ◽  
Luciana Previato ◽  
Agustin Carbajal ◽  
Courtney T. Griffin ◽  
...  
Keyword(s):  
Germ Cell ◽  
Cell Survival ◽  
Chromatin Remodeling ◽  
Male Gamete ◽  
Stem Cell Population ◽  
Nurd Complex ◽  
Nucleosome Remodeling ◽  
Testis Development ◽  
Expression Of Genes ◽  
Chromatin Remodeling Complexes

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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