G9a/GLP-Sensitivity of H3K9me2 Demarcates Two Types of Genomic Compartments

Abstract

In the nucleus, chromatin is folded into hierarchical architecture that is tightly linked to various nuclear functions. However, the underlying molecular mechanisms that confer these architectures remain incompletely understood. Here, we investigated the functional roles of H3 lysine 9 dimethylation (H3K9me2), one of the abundant histone modifications, in three-dimensional (3D) genome organization. Unlike mouse embryonic stem cells (mESCs), inhibition of methyltransferases G9a and GLP in differentiated cells eliminated H3K9me2 predominantly at A-type (active) genomic compartments, and the level of residual H3K9me2 modification was strongly associated with genomic compartments in differentiated cells. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes led to the decreased chromatin-nuclear lamina interactions mainly at G9a/GLP sensitive regions (GSRs), the increased degree of genomic compartmentalization, and the up-regulation of hundreds of genes that were associated with alterations of the 3D chromatin. Collectively, our data demonstrated essential roles of H3K9me2 in 3D genome organization.