SREBF1 coordinates with master transcription factors in regulating lipid metabolism and cancer-promoting pathways in squamous cell carcinoma [4C]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE178923 | GEO | 2021/06/26
REPOSITORIES: GEO
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Project description:Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that the transcription factors TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. Our recent study have identified TP63 and SOX2 as super-enhancer-associated genes. However, functional consequences of their frequent co-localization at super-enhancers region remains unexplored. Here, ChIP-seq result indicated TP63 and SOX2 co-occupied peaks are significantly located the super enhancer region compare with unique of TP63 and SOX2 signaling, and combined RNA-seq analyses of different types of SCCs reveal that TP63 and SOX2 cooperatively regulate expression of the super-enhancer-associated the long non-coding RNA (lncRNA) gene, CCAT1. CCAT1 is highly expressed in SCCs compared to either other tumor types or normal tissues. CCAT1 expression strongly correlates with expression levels of TP63 and SOX2. Silencing of CCAT1 significantly reduces cellular growth both in vitro and in vivo, phenotyping the effect of silencing either TP63 or SOX2. Furthermore, ChIP-Seq and luciferase reporter assays demonstrate TP63 and SOX2 co-occupy the promoter and super-enhancer regions of CCAT1. Interaction of CCAT1 with TP63 and SOX2 are validated by RNA immunoprecipitation. In addition, ChIRP analysis suggests that CCAT1 regulates EGFR expression by binding to the super-enhancer of EGFR. Further investigations shows that CCAT1 activates both the MEK/ERK1/2 and PI3K/AKT signaling pathways through up-regulation of EGFR. In conclusion, CCAT1 is driven by master transcription factors TP63 and SOX2 and is recruited to the super-enhancer of EGFR, promoting SCC tumorigenesis through activation of the MEK/ERK1/2 and PI3K/AKT signaling pathways. These studies help to explain the pathogenesis of SCC and aids in providing novel therapeutic strategy.
2018-09-17 | GSE106564 | GEO
Project description:Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that the transcription factors TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. Our recent study have identified TP63 and SOX2 as super-enhancer-associated genes. However, functional consequences of their frequent co-localization at super-enhancers region remains unexplored. Here, ChIP-seq result indicated TP63 and SOX2 co-occupied peaks are significantly located the super enhancer region compare with unique of TP63 and SOX2 signaling, and combined RNA-seq analyses of different types of SCCs reveal that TP63 and SOX2 cooperatively regulate expression of the super-enhancer-associated the long non-coding RNA (lncRNA) gene, CCAT1. CCAT1 is highly expressed in SCCs compared to either other tumor types or normal tissues. CCAT1 expression strongly correlates with expression levels of TP63 and SOX2. Silencing of CCAT1 significantly reduces cellular growth both in vitro and in vivo, phenotyping the effect of silencing either TP63 or SOX2. Furthermore, ChIP-Seq and luciferase reporter assays demonstrate TP63 and SOX2 co-occupy the promoter and super-enhancer regions of CCAT1. Interaction of CCAT1 with TP63 and SOX2 are validated by RNA immunoprecipitation. In addition, ChIRP analysis suggests that CCAT1 regulates EGFR expression by binding to the super-enhancer of EGFR. Further investigations shows that CCAT1 activates both the MEK/ERK1/2 and PI3K/AKT signaling pathways through up-regulation of EGFR. In conclusion, CCAT1 is driven by master transcription factors TP63 and SOX2 and is recruited to the super-enhancer of EGFR, promoting SCC tumorigenesis through activation of the MEK/ERK1/2 and PI3K/AKT signaling pathways. These studies help to explain the pathogenesis of SCC and aids in providing novel therapeutic strategy.
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Project description:To characterize enhancer elements regulating the MEF2C gene during neurodevelopment, we performed among others Circularized Chromosome Conformation Capture (4C) sequencing in a neuronal cell line, SH-SY5Y, and a non-neuronal control, HEK. We found that, in a neuronal cell line, the MEF2C promoter interacts with several putative enhancer elements in its upstream region, forming a complex interaction network. Moreover, these interactions are completely absent in HEK cells.
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Project description:We profiled esophageal squamous cell carcinorma (ESCC) cell lines with chromatin immunoprecipitation sequencing (ChIP-Seq). Mathematically modeling was performed to establish (super)-enhancers landscapes and inter-connected transcriptional circuitry formed by master TFs. Coregulation and cooperation between master TFs was investigated by ChIP-Seq, RNASeq, 4C-Seq and luciferase assay. Biological functions of candidate factors were evaluated by measuring cell proliferation, colony formation, cell apoptosis and xenograft growth. Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. Here, we aim to compare of ESCC cells knock down SREBF1 with siRNA and negative control transcriptome profiling (RNA-seq) to microarray and quantitative reverse transcription polymerase chain reaction (qRT–PCR) methods and to evaluate protocols for optimal high-throughput data analysis. We also report the application of circular chromatin conformation capture (4C) sequencing technology for studying master transcription factor (SREBF1) in human ESCC cancer cell lines (TE5).
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Project description:Super-enhancers may regulate target genes through chromatin looping. We connected super-enhancers in the K562 chronic myelogenous leukemia cell line with chromatin interactions identified from Chromatin Interaction Analysis with Paired-End Tag (ChIA-PET) data. Gene expression at proximal elements that are connected with distal super-enhancers showed significantly higher cell-type specificity than at proximal elements connected with other elements or not involved in interaction. 4C and Episwitch analysis of chromatin interactions showed that certain chromatin interactions are cell-specific, but others are more general. While super-enhancers upstream of c-MYC at the MYC-335 element can be found in other cancers, only super-enhancers downstream of c-MYC can be found in K562. 4C analysis of the c-MYC promoter revealed no chromatin interactions that are directed upstream of c-MYC, but only downstream of c-MYC, in the PVT1 long non-coding RNA gene. Cell-specific usage of super-enhancers could explain why the MYC-335 element that is associated with many solid cancers such as colorectal cancer and breast cancer, but not with leukemia. Surprisingly, we found that a chromatin interaction between c-MYC and a c-MYC super-enhancer is lost in chronic myelogenous leukemia patient blood as compared with blood from individuals without the disease through Oxford Biodynamicsâ?? Episwitch analysis. These results provide evidence for fine-tuning of expression patterns, such as cell-specific regulation of target genes by distal super-enhancers through chromatin interactions and an association between chromatin interactions and disease, and highlight that super-enhancers are more complex than previously described. Examination of several chromatin interactions involving super-enhancers using 4C-Seq and Episwitch (TM)
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Project description:Mouse Bcell, upon ectopic expression of the transcription factor Cebpa for 18h, can be reprogrammed to iPS with extremely high efficiency. To understand the molecular control of this phenomena we performed multiple high throughtput functionnal genomic analysis. Circularized chromosome conformation capture assay (4C) taking as view point Klf4 promoter and a putative enhancer situated a -100kb upstream
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Project description:One of the strongest associated type 2 diabetes (T2D) loci reported to date resides within the TCF7L2 gene. Previous studies point to the T allele of rs7903146 in intron 3 as the causal variant at this locus. To aid in the identification of the actual gene(s) under the influence of this variant, we first generated a CRISPR/Cas9 mediated 1.4kb deletion of the genomic region harboring rs7903146 in the HCT116 cell line followed by global gene expression analysis (see experiment E-MTAB-4839). We then carried out high-throughput chromosome conformation capture assays in the HCT116 and NCM460 cell lines and in colon tissue in order to ascertain which of these perturbed genes promoters made consistent physical contact with the genomic region harboring the variant. To assess consistency and reproducibility we utilized two different techniques: Circularized Chromosome Conformation Capture (4C) and Capture C. In both types of assays, after preparing 3C libraries, our bait of interest was the region harboring rs7903146. Loci interacting with such bait are enriched for by inverse PCR in 4C and by oligonucleotide capture in capture C. 4C assays were carried out in the following samples: two on NCM460 cells (using different primer sets), one on HCT116 cells, one on HCT116 cells with a CRISPR/Cas9 mediated 1.4kb deletion of the genomic region harboring the SNP rs7903146, and one on colon tissue. Capture C assays were carried out in one sample each of the cell lines NCM 460 and HCT116. This experiment, coupled with the associated E-MTAB-4839, revealed just one gene, ACSL5, which resides in the same topologically associating domain as TCF7L2.
2016-08-15 | E-MTAB-4845 | biostudies-arrayexpress
Project description:CRTC2 is a critical transcription cofactor that induces the glucose homeostatic genes by activating CREB. However, energy homeostasis is maintained by multiple pathways, therefore, it is possible that CRTC2 may interact with other transcription factors, especially under metabolic stress. Thereby, CRTC2 liver-specific knockout mice were created and the global proteome, phosphoproteome and acetylome from liver tissue under the high fat diet conditions were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis. As expected, differentially expressed proteins (DEPs) are enriched in metabolic pathways that were subsequently corroborated by animal experiments. The consensus DEPs from these datasets were used as seed proteins to generate a protein-protein interaction (PPI) network using STRING and GeneMANIA identified fatty acid synthase (FASN) as the mutually relevant protein. Additional local-PPI (LPPI) analysis of CRTC2 and FASN with DEPs, SREBF1 was found to be a common mediator. CRTC2/CREB and SREBF1 are transcription factors, DNA-binding motif analysis showed multiple CRTC2/CREB regulated genes also possess SREBF1 binding motifs that unveil the possible induction by CRTC2/SREBF1 complex, which is reinforced by structural analysis. Thus, CRTC2/SREBF1 complex plausibly modulate the transcription of multiple proteins that fine-tune the cellular metabolism under metabolic stress.
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