CpG island-mediated global gene regulatory modes in mouse embryonic stem cells.

Samuel Beck,Jonghwan Kim,Catherine Rhee,Bum-Kyu Lee,Jawon Song,Andrew J Woo

doi:10.1038/ncomms6490

Abstract

Both transcriptional and epigenetic regulations are fundamental for the control of eukaryotic gene expression. Here we perform a compendium analysis of >200 large sequencing data sets to elucidate the regulatory logic of global gene expression programs in mouse embryonic stem (ES) cells. We define four major classes of DNA-binding proteins (Core, PRC, MYC and CTCF) based on their target co-occupancy, and discover reciprocal regulation between the MYC and PRC classes for the activity of nearly all genes under the control of the CpG island (CGI)-containing promoters. This CGI-dependent regulatory mode explains the functional segregation between CGI-containing and CGI-less genes during early development. By defining active enhancers based on the co-occupancy of the Core class, we further demonstrate their additive roles in CGI-containing gene expression and cell type-specific roles in CGI-less gene expression. Altogether, our analyses provide novel insights into previously unknown CGI-dependent global gene regulatory modes.

Highlights

Both transcriptional and epigenetic regulations are fundamental for the control of eukaryotic gene expression
We showed that the reciprocal regulation between the MYC and polycomb repressive complex (PRC) classes is predominant in CpG island (CGI) þ genes and controls the general activity of almost all CGI þ genes (Fig. 3)
Unlike previous reports[19,30], we found that a large portion of the CGI þ promoters remained bivalent even in differentiated tissues (Supplementary Fig. 3b), suggesting that the reciprocal regulation of CGI þ genes by the MYC and PRC classes may be a common feature shared in other cellular contexts

Summary

Introduction

Both transcriptional and epigenetic regulations are fundamental for the control of eukaryotic gene expression. We define four major classes of DNA-binding proteins (Core, PRC, MYC and CTCF) based on their target co-occupancy, and discover reciprocal regulation between the MYC and PRC classes for the activity of most genes under the control of the CpG island (CGI)-containing promoters This CGI-dependent regulatory mode explains the functional segregation between CGI-containing and CGI-less genes during early development. In addition to the identification of core transcription factors (TFs), such as OCT4, SOX2 and NANOG8–11, subsequent studies on the expansion of transcriptional regulatory circuitry have suggested that global gene expression regulation in ES cells is achieved by functionally separable regulatory sub-modules[12,13] This modular regulation requires close interactions between multiple DBPs including TFs and chromatin regulators and a distinct set of their chromosomal targets. Our findings provide novel insights into CGI-dependent global gene regulatory modes in ES cells, characterized by the general regulation of CGI þ promoters by the MYC and PRC classes, and the tissue-specific regulation of CGI À genes by enhancer binding Core class DBPs

Methods

Results

Conclusion