CHD7 Regulates Bone-fat Balance via Suppressing PPAR-γ Signaling Pathway
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA705462 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13806000_1.fastq.gz | Fastqsanger.gz | |||
| SRR13806000_2.fastq.gz | Fastqsanger.gz | |||
| SRR13806001_1.fastq.gz | Fastqsanger.gz | |||
| SRR13806001_2.fastq.gz | Fastqsanger.gz | |||
| SRR13806002_1.fastq.gz | Fastqsanger.gz |
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Project description:Chromodomain helicase DNA-binding protein 7 (CHD7) is an ATP-dependent eukaryotic chromatin remodeling enzyme that plays a critical role in epigenetics. Previous studies showed CHD7 is essential in development of organs and mutation of CHD7 is the main cause of CHARGE syndrome, but the function of CHD7 in skeletal system remained elusive. Here we show that conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and pre-osteoblasts leads to a pathological phenotype in mice, manifested as skeletal system development disorder, low bone mass and severely high marrow adiposity. Mechanistically, we identify up-regulated peroxisome proliferators-activated receptors (PPAR) signaling pathway in Chd7-deficient MSCs. Knockout of Chd7 reduces the restriction of PPAR-γ, then PPAR-γ associates with tri-methylated histone H3 at lysine 4 (H3K4me3), activates the transcription of the downstream adipogenic genes, and disrupts the balance between osteogenic and adipogenic differentiation. Our work illustrates the pathological manifestations of Chd7 mutation in MSCs and reveals novel epigenetic mechanism in skeletal health and diseases.
2022-02-28 | GSE167886 | GEO
Project description:Chromodomain helicase DNA-binding protein 7 (CHD7), an ATP-dependent eukaryotic chromatin remodeling enzyme, is essential for the development of organs. The mutation of CHD7 is the main cause of CHARGE syndrome, but its function and mechanism in skeletal system remain unclear. Here, we show conditional knockout of Chd7 in bone marrow mesenchymal stem cells (MSCs) and preosteoblasts leads to a pathological phenotype manifested as low bone mass and severely high marrow adiposity. Mechanistically, we identify enhancement of the peroxisome proliferator-activated receptor (PPAR) signaling in Chd7-deficient MSCs. Loss of Chd7 reduces the restriction of PPAR-γ and then PPAR-γ associates with trimethylated histone H3 at lysine 4 (H3K4me3), which subsequently activates the transcription of downstream adipogenic genes and disrupts the balance between osteogenic and adipogenic differentiation. Our data illustrate the pathological manifestations of Chd7 mutation in MSCs and reveal an epigenetic mechanism in skeletal health and diseases.
| S-EPMC9007978 | biostudies-literature
Project description:Pharmacological activation of the transcription factor PPAR gamma lowers blood pressure and improves glucose tolerance in humans. In contrast, naturally occurring mutations (e.g., P467L, V290M) in the ligand binding domain of PPAR gamma in humans leads to severe insulin resistance and early-onset hypertension. Experimental evidence, including whole genome expression profiling, suggests that these mutant versions of PPAR gamma act in a dominant negative manner. Because PPAR gamma is expressed in a variety of cell types and tissues, we generated a transgenic mouse model (SP467L) specifically targeting dominant negative PPAR gamma to the vascular smooth muscle cells in order to determine the action of PPAR gamma in the blood vessel independent of its systemic metabolic actions. In the data set provided herein, we examined the gene expression profile in mesenteric vessels from SP467L mice and their control littermates using the Affymetrix mouse exon 1.0 ST array.
2012-09-24 | GSE36482 | GEO
Project description:CHD7 is a member of the chromodomain helicase DNA binding domain family of ATP-dependent chromatin remodeling enzymes. De novo mutation of the CHD7 gene is a major cause of CHARGE syndrome, a genetic disease characterized by a complex constellation of birth defects. To gain insight to the function of CHD7, we mapped the distribution of the CHD7 protein on chromatin using the approach of chromatin immunoprecipitation on tiled microarrays (ChIP-chip). These studies were performed in human colorectal carcinoma cells, human neuroblastoma cells, and mouse embryonic stem (ES) cells before and after differentiation into neural precursor cells. The results indicate that CHD7 localizes to discrete locations along chromatin that are specific to each cell type, and that the cell-specific binding of CHD7 correlates with a subset of histone H3 methylated at lysine 4 (H3K4me). The CHD7 sites change concomitantly with H3K4me patterns during ES cell differentiation, suggesting that H3K4me is part of the epigenetic signature that defines lineage-specific association of CHD7 with specific sites on chromatin. Furthermore, the CHD7 sites are predominantly located distal to transcription start sites, most often contained within DNase hypersensitive sites, frequently conserved, and near genes expressed at relatively high levels. These features are similar to those of gene enhancer elements, raising the possibility that CHD7 functions in enhancer mediated transcription, and that the congenital anomalies in CHARGE syndrome are due to alterations in transcription of tissue-specific genes normally regulated by CHD7 during development. ChIP-chip experiments were performed for CHD7 and H3K4 mono-,di-, and trimethylation modifications in 4 cells types: human DLD1 and SH-SY5Y; mouse ES and differentiated neural precursor cells derived from mouse ES cells. Microarrays used in these experiments tiled all or subset of ENCODE regions (in mouse, analogous ENCODE regions were assayed). At least two biological replicates were performed for each CHD7 ChIP experiment; H3K4 ChIP's were performed once in each cell type.
2009-01-22 | E-GEOD-14460 | biostudies-arrayexpress
Project description:The rising prevalence of obesity and its associated metabolic abnormalities have become global diseases that carry considerable morbidity and mortality. While there is certainly an important genetic component, extensive human epidemiologic and animal model data suggest an epigenetic component to obesity. Nevertheless, the cellular and molecular underpinnings of these pathways and how they contribute to the development of obesity remain to be elucidated. Suv420h1 and h2 are histone methyltransferases responsible for chromatin compaction and gene repression. Through in vivo, ex-vivo and in vitro studies, we found that Suv420h1 and h2 respond to environmental stimuli and regulate metabolism by downregulating PPAR-γ, a master transcriptional regulator of lipid storage and glucose metabolism. Accordingly, mice lacking Suv420h proteins activate PPAR-γ target genes in brown adipose tissue to increase mitochondria respiration, improve glucose tolerance and reduce adipose tissue to fight obesity. We conclude that Suv420h proteins are key epigenetic regulator of PPAR-γ and the pathways controlling metabolism and weight balance in response to environmental stimuli.
2019-04-23 | GSE117482 | GEO
Project description:Oligodendrocyte precursor cells (OPCs) constitute the main proliferative cells in the adult brain, and deregulation of OPC proliferation-differentiation balance results in either glioma formation or defective adaptive (re)myelination. OPC differentiation requires significant genetic reprogramming implicating chromatin remodeling. Here, we report on uncharacterized functions of the chromatin remodelers Chd7 and Chd8 in OPCs. Their OPC-chromatin-binding profile combined with transcriptome and open-chromatin analysis of Chd7-deleted OPCs, demonstrates that Chd7 controls OPC differentiation through chromatin-opening and transcriptional activation of key regulators such as Sox10, Nkx2.2 and Gpr17. Chd7 is however dispensable for oligodendrocyte stage progression, consistent with Chd8 compensatory function, as suggested by its chromatin binding profile. Furthermore, Chd7 protects non-proliferative OPCs from apoptosis by chromatin-closing and transcriptional repression of p53. Mutations in CHD7 and CHD8 are associated with developmental disorders, such as CHARGE syndrome and autism respectively, and our results offer new avenues to understand and modulate their functions in disease.
2018-08-29 | GSE116598 | GEO
Project description:Gene expression changes were measured between mouse ES cells of three genotypes: WT Chd7, Heterzygous Chd7 Null, Homozygous Chd7 Null. The hypothesis being tested was that CHD7, a chromatin remodeling protein, functions as a transcriptional regulator. This experiment was performed to detect gene targets of CHD7-mediated regulation. We report the genome-wide binding profile of CHD7, the protein implicated in CHARGE syndrome, in mouse ES cells using ChIP-Seq technology. Combining these data with other genomic datasets, we discover CHD7 to colocalize with other transcription factors including Oct4, Nanog, Sox2, and p300 at gene enhancer elements to regulate ES cell specific gene expression. Chd7 wildtype, heterozygous, and homozygous ES cells derived from preimplantation embryos were grown on feeder cells and total RNA was isolated using Trizol. The ratio of ES to feeder cells was estimated at 5:1. ChIP sequencing of CHD7 and p300 in mouse ES cells
2010-06-15 | E-GEOD-22341 | biostudies-arrayexpress
Project description:Pharmacological activation of the transcription factor PPAR gamma lowers blood pressure and improves glucose tolerance in humans. In contrast, naturally occurring mutations (e.g., P467L, V290M) in the ligand binding domain of PPAR gamma in humans leads to severe insulin resistance and early-onset hypertension. Experimental evidence, including whole genome expression profiling, suggests that these mutant versions of PPAR gamma act in a dominant negative manner. Because PPAR gamma is expressed in a variety of cell types and tissues, we generated a transgenic mouse model (SP467L) specifically targeting dominant negative PPAR gamma to the vascular smooth muscle cells in order to determine the action of PPAR gamma in the blood vessel independent of its systemic metabolic actions. In the data set provided herein, we examined the gene expression profile in mesenteric vessels from SP467L mice and their control littermates using the Affymetrix mouse exon 1.0 ST array. We generated transgenic mice specifically targeting expression of mutant dominant negative human PPAR gamma (P467L) to vascular smooth muscle using a smooth muscle-specific promoter (smooth muscle myosin heavy chain or SMMHC). Mesenteric arteries were isolated from 3 male transgenic mice and 4 non-transgenic littermate controls. Total RNA was prepared using conventional methods and quality was assessed using the Bioanalyzer 2100 (Agilent Technologies). For the microarray hybridizations, each sample corresponded to mesenteric artery derived from one mouse. All procedures were conducted at the University of Iowa DNA Core facility using standard Affymetrix protocols. In brief, approximately 50 ng of total RNA was used as input to a two-step amplification procedure (NuGen, http://www.nugeninc.com/) to generate biotin-labeled RNA fragments for hybridization to the Affymetrix mouse exon 1.0 ST array.
2012-09-24 | E-GEOD-36482 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE37194: Gene expression profiling during interference with PPAR gamma signaling in thoracic aorta GSE37195: Gene expression profiling using exon arrays during interference with PPAR gamma signaling in thoracic aorta Refer to individual Series
2012-10-03 | E-GEOD-37196 | biostudies-arrayexpress
Project description:The nuclear receptor PPAR[gamma] is a master regulator controlling energy metabolism and cell fate in the prostate. One advanced human prostate cancer cell line PC3 was used to examine the effects of restoration of PPAR[gamma]2 action. Restoration of PPAR[gamma]2 action in PC3 cells inhibited cell proliferation and migration. PC3-PPAR[gamma]2 cDNA recombinants showed necrosis in cancer region and lymphocyte infiltration in surrounding stroma by H&E staining. They expressed low microtubules associated protein 1 light chain 3 (LC3), and high mixed lineage kinase domain-like (MLKL), CD4 and CD8 protein expression levels compare to the control by IHC staining. Gain-of-function of PPAR[gamma]2 in PC3 cells resulted in reprogramming of lipid and energy metabolism-associated signaling pathways by microarray analysis. These data are consistent with the idea that PPAR[gamma] action specific to PPAR[gamma]2, exerts a crucial tumor suppressive role on triggering autophagy and necroptosis in human prostate cancer initiation and progression.
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