Butyrate Induced IGF2 Activation Correlated with Distinct Chromatin Signatures Due to Histone Modification

Abstract

Histone modification has emerged as a very important mechanism regulating the transcriptional status of the genome. Insulin-like growth factor 2 (IGF2) is a peptide hormone controlling various cellular processes, including proliferation and apoptosis. H19 gene is closely linked to IGF2 gene, and IGF2 and H19 are reciprocally regulated imprinted genes. The epigenetic signature of H19 promoter (hypermethylation) on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2.46 Our previous studies demonstrate that butyrate regulates the expression of IGF2 as well as genes encoding IGF Binding proteins. To obtain further understanding of histone modification and its regulatory potentials in controlling IGF2/H19 gene expression, we investigated the histone modification status of some key histones associated with the expression of IGF2/H19 genes in bovine cells using RNA-seq in combination with Chip-seq technology. A high-resolution map of the major chromatin modification at the IGF2/H19 locus induced by butyrate was constructed to illustrate the fundamental association of the chromatin modification landscape that may play a role in the activation of the IGF2 gene. High-definition epigenomic landscape mapping revealed that IGF2 and H19 have distinct chromatin modification patterns at their coding and promoter regions, such as TSSs and TTSs. Moreover, the correlation between the differentially methylated regions (DMRs) of IGF2/H19 locus and histone modification (acetylation and methylation) indicated that epigenetic signatures/markers of DNA methylation, histone methylation and histone acetylation were differentially distributed on the expressed IGF2 and silenced H19 genes. Our evidence also suggests that butyrate-induced regional changes of histone acetylation statusin the upstream regulation domain of H19 may be related to the reduced expression of H19 and strong activation of IGF2. Our results provided insights into the mechanism of butyrate-induced loss of imprinting (LOI) of IGF2 and regulation of gene expression by histone modification.

Use of Sodium Butyrate as an Alternative to Dietary Fiber: Effects on the Embryonic Development and Anti-Oxidative Capacity of Rats

“…Inhibition of histone deacetylases represents one of the mechanisms of GST activation by butyrate, which explains the possible role of butyrate on antioxidant related gene expression [57] . To the best of our knowledge, the imprint gene IGF2 plays an important role on placenta transporter expression and fetus growth, with butyrate being involved in the induction of Igf-2 activation and regulation of gene expression by histone modification [58] .…”

Alteration of Metabolic Conditions Impacts the Regulation of IGF-II/H19 Imprinting Status in Prostate Cancer

“…Loss of imprinting in the growth factor, IGF-II, is a phenomenon common to many different cancer types [ 39 ]. The causes and consequences remain unclear.…”

Loss of imprinting of IGF2 in fibroadenomas and phyllodes tumors of the breast

“…Noteworthy, the imprinting status of the epithelial cells and stromal cells in each tumor was identical, i.e., every tumor consisted of either LOI + epithelial cells and LOI + stromal cells or LOIepithelial cells and LOIstromal cells. It has been reported that LOI can be induced by treatment with butyrate, which modifies histone acetylation (5). Furthermore, oxidative stress reportedly induces NF-κb binding to the CCCTC-binding factor (CTCF) promoter, which then leads to reduced CTCF expression, loss of CTCF binding to the ICR and IGF2 LOI (30).…”

“…The IGF2 gene is located within the IGF2/H19 imprinted gene cluster on chromosome 11p15 and is expressed predominantly from the paternal allele (2)(3)(4). IGF2 promotes the growth and proliferation of cells in many different tissues (5) and is highly expressed in various types of tumors (6)(7)(8) including fibroepithelial tumors of the breast (1). As reported in studies of Wilms' tumors, loss of IGF2 imprinting (LOI) manifested by biallelic gene expression results in IGF2 overexpression and subsequent tumor formations (9,10).…”