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 in mouse embryonic stem cells, inhibition of methyltransferases G9a and GLP in differentiated cells eliminated H3K9me2 predominantly at A-type (active) genomic compartments, and the level of residual H3K9me2 modifications was strongly associated with B-type (inactive) genomic compartments. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes led to decreased chromatin-nuclear lamina interactions mainly at G9a/GLP-sensitive regions, increased degree of genomic compartmentalization, and 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.

G9a Inhibition Promotes Neuroprotection through GMFB Regulation in Alzheimer’s Disease

“…We next sought to further characterize the dynamics of the histone mark H3K9me2 after treatment with a G9ai. We used public H3K9me2 ChIP-seq data corresponding to AML12 cells (murine hepatocyte cell line) treated with UNC0638, a selective G9ai[ 45 ] with the same specificity as UNC0642. Analysis of H3K9me2 enrichment revealed the presence of this histone mark in distal regions (60.78%) and promoters (13.65%) in cells treated with the G9ai ( Fig.…”

“…Publicly available H3K9me2 ChIP-seq data corresponding to AML12 cells (murine hepatocyte cell line) treated with the selective G9a inhibitor, UNC0638[ 45 ] were obtained from the Genome Sequence Archive (GSA: CRA002762)[ 46 ]. ChIP-seq analysis was performed as previously described[ 47 ].…”

Uncovering the role of G9a modulatory landscape promoting neuronal plasticity and neuroprotection in Alzheimer's disease

“…Publicly available H3K9me2 ChIP-seq data corresponding to AML12 cells (murine hepatocyte cell line) treated with the selective G9a inhibitor, UNC0638 39 were obtained from the Genome Sequence Archive (GSA: CRA002762) 69 . ChIP-seq analysis was performed as previously described 70 .…”

The cancer epigenome: Non‐cell autonomous player in tumor immunity

“…The latest integrated 3D epigenome analysis suggests compartment‐specific epigenetic machinery and distinct function mediated by G9a/GLP‐dependent H3K9me2 35 . For instance, the G9a/GLP complex mainly deposits H3K9me2 in compartment A (euchromatin) or B (heterochromatin) in mESCs or mouse liver cells, respectively, 35,36 suggesting that G9a/GLP‐dependent H3K9me2 contributes to lineage differentiation states through distinct repressive 3D chromatin states. A distinct function of G9a‐dependent H3K9me2 has been termed “large organized chromatin K9‐modifications” (LOCKs), which are implicated in a differentiation state, and almost all H3K9me3 marks do not overlap LOCKs 37 .…”

“…or mouse liver cells, respectively, 35,36 suggesting that G9a/GLPdependent H3K9me2 contributes to lineage differentiation states through distinct repressive 3D chromatin states. A distinct function of G9a-dependent H3K9me2 has been termed "large organized chromatin K9-modifications" (LOCKs), which are implicated in a differentiation state, and almost all H3K9me3 marks do not overlap LOCKs.…”