Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

Abstract

Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR, we performed ChIP-Seq to identify and map genome-wide histone modifications and gene dysregulation in islets from 2- and 10-week rats. IUGR induced significant changes in the enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in both 2-wk and 10-wk islets, which were correlated with expression changes of multiple genes critical for islet function in IUGR islets. ChIP-Seq analysis showed that IUGR-induced histone mark changes were enriched at critical transcription factor binding motifs, such as C/EBPs, Ets1, Bcl6, Thrb, Ebf1, Sox9, and Mitf. These transcription factors were also identified as top upstream regulators in our previously published transcriptome study. In addition, our ChIP-seq data revealed more than 1000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. The poised state of many potential bivalent genes was altered by IUGR, particularly Acod1, Fgf21, Serpina11, Cdh16, Lrrc27, and Lrrc66, key islet genes. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes that may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.

Proteomics and Metabolomics Profiling of Platelets and Plasma Mediators of Thrombo-Inflammation in Gestational Hypertension and Preeclampsia

“…Next, we addressed whether PE can be distinguished from GH at the initial finding of hypertension by assessing biomarkers at time of diagnosis. Unique to PE was the overexpression in platelets of leucine-rich repeat-containing proteins 27/42 (LRRC27/42) [33,34], two proteins with limited characterization that could play biological roles in cell adhesion, signal transduction and apoptosis, and S100A9, a Ca 2+ and Zn 2+ protein regulating inflammation and immune responses [35,36], which we functionally validated. Lastly, we utilized pathway analysis to generate a new hypothesis for platelets' contribution to the thrombo-inflammatory state of preeclampsia.…”

A Pan-Cancer Analysis Revealing the Dual Roles of Lysine (K)-Specific Demethylase 6B in Tumorigenesis and Immunity

“…In addition to catalytically removing the methyl groups from H3K27me3, KDM6B also bonded to the Set1/MLL H3K4 methyltransferase complex to activate gene transcription ( Shi et al, 2014 ; Yu et al, 2018 ). H3K4 trimethylation was associated with transcriptional activation, while H3K27 trimethylation contributed to transcriptional silencing ( Lien et al, 2020 ). Hypermethylation of the proto-oncogene H3K4 may activate transcription of oncogenes and other cancer-associated genes, eventually contributing to the development and progression of tumors ( Li et al, 2017 ).…”

Epigenetic Regulation of β Cell Identity and Dysfunction

“…The acetylation of histones have been associated with islet development, function, and the development of T2DM. Histone H3 lysine 27 acetylation (H3K27ac), a mark associated with active enhancers, is decreased in both 2-week and 10-week intrauterine growth retardation (IUGR) rats which is associated with increased risk of adulthood T2DM (15). The association between H3K27Ac, gene expression changes, and functional defects in pancreatic islets have been described in high fat diet induced obese mice (16).…”