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Sodium arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in mouse embryonic fibroblast cells

ABSTRACT: Both epidemiological investigations and animal studies have linked arsenic-contaminated water to cancers, in- cluding skin, liver and lung cancers. Besides genotoxicity, arsenic exposure-related pathogenesis of disease is widely considered through epigenetic mechanisms; however, the underlying mechanism remains to be deter- mined. Herein we explore the initial epigenetic changes via acute sodium arsenite (As) exposures of mouse em- bryonic fibroblast (MEF) cells and histone H3K79 methyltransferase Dot1L knockout (Dot1L−⁠ /−) MEF cells. Our RNA-seq and Western blot data demonstrated that, in both cell lines, acute As exposure abolished histone acetyl- transferase p300 at the RNA level and subsequent protein level. Consequently, p300-specific main target histone H3K27ac, a marker separating active from poised enhancers, decreased dramatically as validated by both West- ern blot and ChIP-qPCR/seq analyses. Concomitantly, H3K4me1 as another well-known marker for enhancers also showed significant decreases, suggesting an underappreciated crosstalk between H3K4me1 and H3K27ac involved in As exposure. Significantly, As exposure-reduced H3K27ac and H3K4me1 inhibited the expression of genes including EP300 itself and Kruppel Like Factor 4(Klf4) that both are tumor suppressor genes. Collectively, our investigations identified p300 as an internal bridging factor within cells to sense external environmental As exposure to alter chromatin, thereby changing gene transcription for disease pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE118827 | GEO | 2020/12/10

REPOSITORIES: GEO

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Project description:Developmental exposures play a role in adult onset chronic disease. The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to chronic disease are not understood. arsenic exposure via drinking water causes cancer and cardiovascular disease. Transplacental arsenic exposure accelerates and exacerbates atherosclerosis in ApoE-knockout mice. The liver plays a central role in the interlinked diseases diabetes, metabolic syndrome and atherosclerosis. The hypothesis that accelerated atherosclerosis is a consequence of altered hepatic development was investigated by microarray profiling of mRNA and microRNA abundance in livers isolated from 10 week old (PND70) and newborn (PND1) mice exposed or not exposed to arsenic from day 8 post-fertilization to birth. The results show that arsenic exposure alters the trajectory of both mRNA and microRNA expression as mice age. A 51-gene signature of arsenic exposure in both PND1 and PND70 mice was identified. Pathway Architect analysis of this signature identified nodes of interaction including Hspa8, IgM and Hnf4a. Gene ontology analysis of arsenic exposure-altered mRNAs indicated that pathways for gluconeogenesis and glycolysis were suppressed in PND1 mice and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced in PND70 mice. Analysis of promoters of differentially expressed genes identified enriched transcription factor binding sites and cluster analyses revealed groups of genes sharing sets of transcription factor binding sites suggesting common regulation. Srebp1 binding sites are present in ~1/6 of the genes differentially expressed in PND70 livers. Western blot analyses of PND70 liver proteins showed that the inducible form of heat shock protein 70 (Hspa1, Hsp70) and the active form of Srebp1 were induced in arsenic-exposed mice as were plasma AST and ALT levels. These results suggest that transplacental ar

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Sodium arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in mouse embryonic fibroblast cells

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