FOXM1 reversion of aging chromatin accessibility profiles and TEAD4/FOXM1/RHNO1 cis-regulatory elements
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PROVIDER: PRJEB46917 | ENA |
REPOSITORIES: ENA
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Project description:There are nearly fifty forkhead (FOX) transcription factors encoded in the human genome and due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological effects. Here we used ChIP-seq to investigate the genome-wide chromatin binding mechanisms used by the forkhead transcription factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G2 and M phases. However, rather than being recruited through canonical RYAAAYA forkhead binding motifs, FOXM1 binding is directed via CHR elements. FOXM1 binds these elements through protein-protein interactions with the MMB transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX transcription factor which allows it to specifically control cell cycle-dependent gene expression. Examination of FOXM1 binding sites in G2/M U2OS cells
2012-11-05 | E-GEOD-38170 | biostudies-arrayexpress
Project description:Background Genomic variations contribute to the phenotypic diversity of individuals. A number of polymorphisms in protein-coding regions that alter drug efficacy or lead to adverse reactions have been characterized; however, noncoding regions that affect drug responses are largely overlooked, except for a limited number of well-studied enhancers. Results We conducted a quantitative assessment of cis-regulatory elements (CREs) based on transcription initiation profiling of mRNAs and noncoding RNAs, including enhancer RNAs, by using CAGE (Cap Analysis of Gene Expression). Candidate CREs identified in a hepatocellular carcinoma HepG2 cell line with stable expression of drug-responsive transcription factor pregnane X receptor (PXR) were further narrowed down by integrating data of PXR-binding sites in human primary hepatocytes and genome-wide association studies. We found more than 100-fold enrichments of the candidates to genetically associated loci with circulating levels of bilirubin and vitamin D, which implicated a link to adverse reactions of PXR ligands. We uncovered novel enhancers of UGT1A1 and TSKU through CRISPR/Cas9 knockout experiments. We identified alleles altering regulatory activities of UGT1A1 and CYP24A1enhancers by using luciferase reporter assay. Furthermore, our siRNA experiments revealed an unexpected impact of TSKU on the expression of vitamin D-metabolizing enzymes. Conclusions Our transcriptome-based assessment of CREs expanded the list of drug-inducible and PXR-mediated enhancers and super-enhancers. We identified regulatory alleles that alter drug-induced gene expressions, and discovered a novel molecular cascade associated with an adverse reaction. Our results contribute a precise understanding of the noncoding elements of the human genome underlying drug responses.
2025-04-17 | PXD060446 | Pride
Project description:Predictable Engineering of Signal-Dependent Cis-Regulatory Elements
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Project description:The goal of this study is to improve the quality, efficiency, and sustainability of milk production by improving the understanding of the function of cis-regulatory elements in regulating the bovine mammary gland. To this end, we have characterized the non-lactating and lactating mammary gland transcriptomes by whole transcriptome shotgun sequencing (RNA-seq). We will identify cis-regulatory elements in the non-lactating and lactating bovine mammary gland genome-wide. Finally, we will annotate and characterize mammary gland cis-regulatory elements by computational analysis and identify high-resolution genome-wide in vivo footprints of diverse trans-acting-factors (TF), over-represented TF bindings sites and overlapping SNPs.
2021-04-06 | GSE116079 | GEO
Project description:The TEAD (1-4) transcription factors comprise the conserved TEA/ATTS DNA binding domain recognising the MCAT element in the promoters of muscle-specific genes. Despite extensive genetic analysis, the function of TEAD factors in muscle differentiation has proved elusive due to redundancy amongst the family members. Expression of the TEA/ATTS DNA binding domain that acts a dominant negative repressor of TEAD factors in C2C12 myoblasts inhibits their differentiation, while selective shRNA knockdown of TEAD4 results in abnormal differentiation characterised by the formation of shortened myotubes. Chromatin immunoprecipitation coupled to array hybridisation (ChIP-chip) shows that TEAD4 occupies 867 promoters including those of myogenic miRNAs. We show that TEAD factors cooperate with MYOD1 to directly induce Myogenin, CDKN1A and Caveolin 3 expression to promote myoblast differentiation and fusion. RNA-seq identifies a novel set of TEAD4 target genes encoding muscle structural and regulatory proteins and those required for the unfolded protein response. In contrast, TEAD4 represses expression of the growth factor CTGF and Cyclin D1 to promote differentiation. Together these results show that TEAD factor activity is essential for C2C12 cell differentiation and define a novel and nonredundant role for TEAD4 in regulating the unfolded protein response. C2C12 cells were infected with retrotiviral vector expressing Flag-HA-Tagged TEAD4 or with empty control vector and selected in the continouos presence of puromycin. Infected cell populations were then differentiated for 5 days in DMEM medium with 2% horse serum and fixed in 0.4% formaldehyde.
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Project description:We have identified TEAD4 as a key prognosis factor in colorectal cancer. To elucidate the potentail mechanism and function of TEAD4 in colorectal caner, we generated two stable cell lines expressing different shRNA targeting TEAD4 in the mesenchymal-like LoVo cells and the differential genes were detected by microarray. LoVo colorectal cancer cells stably expressing pLKO.1 control shRNA or sh1_shTEAD4 or sh2_shTEAD4
2014-01-01 | E-GEOD-53063 | biostudies-arrayexpress
Project description:In the preimplantation mouse embryo TEAD4 is critical to establishing the trophectoderm (TE)-specific transcriptional program and segregating TE from the inner cell mass (ICM). However, TEAD4 is expressed both in the TE and the ICM. Thus, differential function of TEAD4 rather than expression itself regulates specification of the first two cell lineages. We used ChIP-seq to define genome-wide TEAD4 target genes and asked how transcription of TEAD4 target genes is specifically maintained in the TE. Our analyses revealed an evolutionarily conserved mechanism, in which lack of nuclear localization of TEAD4 impairs the TE-specific transcriptional program in inner blastomeres, thereby allowing their maturation towards the ICM lineage. Restoration of TEAD4 nuclear localization maintains the TE-specific transcriptional program in the inner blastomeres and prevents segregation of the TE and ICM lineages and blastocyst formation. We propose that altered subcellular localization of TEAD4 in blastomeres dictates first mammalian cell fate specification. ChIPseq profiles of TEAD4, IgG, Input in Mouse trophoblast stem cells using Illumina HiSeq 2000 and Illumina Genome Analyzer IIx
2012-04-18 | E-GEOD-37350 | biostudies-arrayexpress
Project description:CRISPR-mediated mutagenesis of RNA editing cis-regulatory elements
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Project description:Characterizing cis-regulatory elements associated with mammary gland function
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