Histone modifications in primary intestinal epithelial cells from wild type (F/FUN) and intesinal NCoR1 deletion (ΔIECUN) neonates.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE86996 | GEO | 2017/03/07
SECONDARY ACCESSION(S): PRJNA343188
REPOSITORIES: GEO
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Project description:Objective: Nuclear receptor action is mediated in part by the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT; also known as NCOR2). NCOR1 and SMRT regulate metabolic pathways that govern body mass, insulin sensitivity and energy expenditure and represent an understudied area in the realm of metabolic health and disease. Previously, we found that NCOR1 and SMRT are essential for maintaining metabolic homeostasis and their knockout (KO) leads to rapid weight loss and hypoglycemia, which is not survivable. Because of a potential defect in glucose absorption, we sought to determine the role of NCOR1 and SMRT specifically in intestinal epithelial cells (IECs). Methods: We used a post-natal strategy to disrupt NCOR1 and SMRT throughout IECs in adult mice. These mice were characterized metabolically by assessing body weight, glucose levels and subjecting the mice to metabolic phenotyping, body composition analysis and glucose tolerance testing. IECs were isolated from the jejunum of the small intestine and profiled by bulk RNA sequencing. Results: We found that the post-natal KO of NCOR1 and SMRT from IECs leads to rapid weight loss and hypoglycemia with a significant reduction in survival. This was accompanied by alterations in glucose metabolism and activation of fatty acid oxidation in IECs. Metabolic phenotyping confirmed a reduction in body mass driven by a loss of body fat without any difference in food intake. This appeared to be driven by a reduction of key intestinal carbohydrate transporters, including SGLT1, GLUT2 and GLUT5. Conclusions: Intestinal NCOR1 and SMRT act in tandem to regulate glucose levels and body weight. This in part may be mediated by regulation of intestinal carbohydrate transporters.
2024-08-12 | GSE268594 | GEO
Project description:Acting downstream of many growth factors, extracellular signal-regulated kinase (ERK) plays a pivotal role in regulating cell proliferation and tumorigenesis, where its spatiotemporal dynamics, as well as its strength, determine cellular responses. Here, we uncover the ERK activity dynamics in intestinal epithelial cells (IECs) and their association with tumour characteristics. In vivo imaging identified two distinct modes of ERK activity, sustained and pulse-like activity, in IECs. The sustained and pulse-like activity depended on ErbB2 and EGFR, respectively. Notably, deregulated activation of Wnt signalling, the earliest event in intestinal tumorigenesis, augmented EGFR signalling and exalted it to a dominant driver of ERK activity dynamics, which rendered IECs addicted to EGFR signalling. Furthermore, the frequency of ERK activity pulses was also increased to promote cell proliferation. Thus, ERK activity dynamics are defined by composite inputs from EGFR and ErbB2 signalling in IECs and their alterations underlie tumour-specific sensitivity to pharmacological EGFR inhibition. In this microarray analysis, we aimed to elucidate molecular mechanisms that mediate Wnt signalling activation-induced alterations in EGFR-ERK signalling dynamics.
2018-02-08 | GSE110257 | GEO
Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function. This SuperSeries is composed of the SubSeries listed below.
2024-02-12 | GSE237654 | GEO
Project description:Corepressors NCOR1 and SMRT regulate metabolism via intestinal regulation of carbohydrate transport
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Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
2024-02-12 | GSE237653 | GEO
Project description:Corepressors negatively regulate gene expression by chromatin compaction. Targeted regulation of gene expression could provide a means to control endothelial cell phenotype. We hypothesize that by targeting corepressor proteins, endothelial angiogenic function can be improved. To study this, the expression and function of nuclear corepressors in human umbilical vein endothelial cells (HUVEC) and in murine organ culture was studied. RNA-seq revealed that nuclear receptor corepressor 1 (NCoR1), Silencing Mediator of Retinoid and Thyroid hormone receptors (SMRT) and repressor element-1 silencing transcription factor (REST) are the highest expressed corepressors in HUVECs. Knockout and knockdown strategies demonstrated that the depletion of NCoR1 increased the angiogenic capacity of endothelial cells, whereas depletion of SMRT or REST did not. Interestingly, the effect was VEGF signaling independent. NCoR1 depletion significantly upregulated angiogenesis-associated genes, especially tip cell genes, including ESM1, DLL4 and NOTCH4, as observed by RNA- and ATAC-seq. Confrontation assays comparing cells with and without NCoR1-deficiency revealed that loss of NCoR1 promotes a tip-cell position during spheroid sprouting. Moreover, a proximity ligation assay identified NCoR1 as a direct binding partner of the Notch-signaling-related transcription factor RBPJk. Luciferase assays showed that siRNA-mediated knockdown of NCoR1 promotes RBPJk activity. Furthermore, NCoR1 downregulation prompts upregulation of several elements in the Notch signaling cascade. Downregulation of NOTCH4, but not NOTCH1, prevented the positive effect of NCoR1 knockdown on spheroid outgrowth. Collectively, these data indicate that decreasing NCOR1 expression is an attractive approach to promote angiogenic function.
2024-02-12 | GSE242671 | GEO
Project description:Intestinal epithelial cells (IECs) were isolated from the colon of Villin-CreERT2, Rnf20-flox and Rnf40-flox mice two weeks upon the Tamoxifen-induced, intestinal knockout of Rnf20 and Rnf40. RNA was isolated from snap-frozen IECs to perform mRNA-seq.
2021-06-16 | E-MTAB-9405 | biostudies-arrayexpress
Project description:Intestinal epithelial cells (IECs) were isolated from the colon of Villin-CreERT2, Rnf20-flox and Rnf40-flox mice two weeks upon the Tamoxifen-induced, intestinal knockout of Rnf20 and Rnf40. ChIP-seq for H3K4me3 was performed using snap-frozen IECs.
2021-06-16 | E-MTAB-9409 | biostudies-arrayexpress
Project description:We profiled transcriptome and accessible chromatin landscapes in intestinal epithelial cells (IECs) from mice reared in the presence or absence of microbiota. We show that regional differences in gene transcription along the intestinal tract were accompanied by major alterations in chromatin organization. Surprisingly, we discovered that microbiota modify host gene transcription in IECs without significantly impacting the accessible chromatin landscape. Instead, microbiota regulation of host gene transcription might be achieved by differential expression of specific TFs and enrichment of their binding sites in nucleosome depleted CRRs near target genes. Our results suggest that the chromatin landscape in IECs is pre-programmed by the host in a region-specific manner to permit responses to microbiota through binding of open CRRs by specific TFs. mRNA and accessible chromatin (DNase-seq) profiles from colonic and ileal IECs were compared between conventionally-raised (CR), germ-free (GF), and conventionalized (CV) C57BL/6 mice.
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Project description:The nuclear corepressors NCOR1 and NCOR2 interact with transcription factors involved in B cell development and potentially link these factors to alterations in chromatin structure and gene expression. Herein we demonstrate that NCOR1/2 deletion limits B cell differentiation via impaired recombination, attenuates pre-BCR-signaling, and enhances STAT5-dependent transcription. Furthermore, NCOR1/2-deficient B cells exhibited derepression of EZH2-repressed gene modules, including the p53 pathway. These alterations resulted in aberrant Rag1 and Rag2 expression and accessibility in proliferating cells. Whole-genome sequencing of Ncor1/2 DKO B cells identified increased number of structural variants compared to wildtype B cells with cryptic recombination signal sequences. Finally, deletion of Ncor1 alleles in mice facilitated leukemic transformation, while human leukemias with less NCOR1 correlated with worse survival. NCOR1 mutations in human leukemia correlated with increased RAG expression and increased number of structural variants. These studies illuminate how the corepressors NCOR1/2 regulate B cell differentiation and provide insights into how NCOR1/2 mutations may promote B cell transformation.
2022-08-30 | GSE208656 | GEO