Butyrate induced IGF2 activation correlated with distinct chromatin landscapes due to histone modification

Authors: SHIN, JOO-HEON - Johns Hopkins University; Li, Robert; GOA, YUAN - Johns Hopkins University; Bickhart, Derek; Liu, Ge - George; LI, WEIZHIONG - University Of California; WU, SITAO - University Of California; Li, Congjun - Cj

Submitted to: PLoS Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/20/2012
Publication Date: 1/22/2013
Citation: Shin, J., Li, R.W., Goa, Y., Bickhart, D.M., Liu, G., Li, W., Wu, S., Li, C. 2013. Butyrate induced IGF2 activation correlated with distinct chromatin landscapes due to histone modification. PLoS Genetics. DOI:10.4137/GRSB.S11243.

Interpretive Summary: Insulin-like growth factor 2 (IGF2) is an important gene for animal growth. Its function depends on specific regulation to activate the gene. The regulation mechanisms are unclear. We used state of the art molecular biology technologies to investigate the regulation mechanisms of this gene. Our results provide insights into the mechanisms of butyrate-induced activation of IGF2 and regulation of gene expression by histone modification.

Technical 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 such as proliferation and apoptosis. IGF2 and H19 are reciprocally regulated imprinted genes. 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 histone associated with the expression of IGF2/H19 genes 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 chromatin modification landscape that may play a role in the activation of 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 status in the up-stream 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.