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Differential DNA Methylation Drives Allelic Architecture for Grb10-Ddc Locus in the Developing Heart

ABSTRACT: While it is understood that the genome is organized into large domains, little is known about cell-type specific interactions at individual loci in mammalian development. Imprinted loci represent a compelling feature of chromatin conformation, illustrating how genes are controlled in local domains to drive parental-specific transcriptional programs important for growth: a clear example being the imprinted Grb10-Ddc locus. Using hybrid mouse crosses and genetic engineering, we uncovered an insulator at Grb10 that is tissue-specific and dynamically controlled by DNA methylation. Insulator CBR2.3 acquires paternal-specific hypomethylation post-implantation, assembling a higher-order structure on the paternal chromosome. Deletion of paternal CBR2.3 converts the chromatin domain to the maternal configuration, redirecting Grb10-Ddc enhancer function, resulting in major cardiac phenotypes. We conclude that CBR2.3 functions as a shared, paternal and tissue-specific insulator for Grb10-Ddc expression in heart, contributing to fundamentally different chromosomal conformations that impact enhancer activity in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE201519 | GEO | 2022/09/14

REPOSITORIES: GEO

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Project description:Background and aims: Liver is a major target organ for alcohol-induced disease and the spectrum of pathological states elicited by alcohol in liver comprises steatosis, alcoholic steatohepatitis, progressive fibrosis and cirrhosis, conditions that may progress to hepatocellular carcinoma. Many experimental animal models of alcoholic steatohepatitis exist that vary in duration, mode of alcohol administration and the degree and types of liver injury produced. While most of these models, regardless whether alcohol is administered through liquid diet or intragastrically, produce steatohepatitis and mild fibrosis, it is widely acknowledged that these models fail to fully recapitulate key characteristics of severe forms of alcoholic liver disease, such as alcoholic hepatitis. Recent studies attempted to combine alcohol and fibrosis and achieved promising results in mouse models that achieve some of the key features of alcoholic liver disease accompanied by exacerbated fibrosis and acute renal injury. This study combined a chronic cholestatic liver fibrosis model induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) with a mouse model of intragastric alcohol feeding. Methods: Adult male C57BL6/J mice were treated with 3,5-diethoxycarbonyl-1,4-dihydrocolidine (DDC) containing diet (0.05% w/w) to induce chronic liver fibrosis. Following DDC-induced fibrogenesis, ethyl alcohol (EtOH) (up to 27 g/ kg/day, up to 28 days) was administered continuously to mice via a gastric feeding tube (Tsukamoto-Frenchmodel of alcoholic liver disease). Results: Exposure to DDC or EtOH alone resulted in liver fibrosis or steatosis, respectively. Combined treatment with DDC and EtOH lead to an additive effect on liver injury, as evident by the development of hepatic inflammation, steatosis, and pericellular fibrosis, and by increased serum transaminase levels, compared to mice treated with either agent alone. Liver transcriptomic changes specific to combined treatment group included pathways involved in the cell cycle and DNA damage. Analyses of feces from these mice revealed alcohol-associated changes to the bile acid profile and gut microbiome. Conclusions: Mice treated with DDC and EtOH displayed several key characteristics of human alcoholic hepatitis, including pericellular fibrosis, increased hepatic bacterial load with dysbiosis, reduced capacity of the microbiome to synthesize secondary bile acids.

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Differential DNA Methylation Drives Allelic Architecture for Grb10-Ddc Locus in the Developing Heart

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