Role of H3K9me3 heterochromatin in cell identity establishment and maintenance

Abstract

Compacted, transcriptionally repressed chromatin, referred to as heterochromatin, represents a major fraction of the higher eukaryotic genome and exerts pivotal functions of silencing repetitive elements, maintenance of genome stability, and control of gene expression. Among the different histone post-translational modifications (PTMs) associated with heterochromatin, tri-methylation of lysine 9 on histone H3 (H3K9me3) is gaining increased attention. Besides its known role in repressing repetitive elements and non-coding portions of the genome, recent observations indicate H3K9me3 as an important player in silencing lineage-inappropriate genes. The ability of H3K9me3 to influence cell identity challenges the original concept of H3K9me3-marked heterochromatin as mainly a constitutive type of chromatin and provides a further level of understanding of how to modulate cell fate control. Here, we summarize the role of H3K9me3 marked heterochromatin and its dynamics in establishing and maintaining cellular identity.

Figure 1. H3K9me3 overview.

(A) Top-to-bottom: representation of H3K9me3 heterochromatin, its function, and the main HMTases responsible for H3K9me3 deposition.

Figure 2. Isolation of srHC though Gradient-seq.

(A) Crosslinked, sonicated chromatin from BJ fibroblasts is separated in distinct fractions in a sucrose gradient to identify sonication-sensitive (euchromatin) and sonication-resistant (srHC) portions of the genome. Sixty-one (61) % of srHC domains are marked by H3K9me3, which is found also in euchromatin (3% of total H3K9me3). Thirty-two (32) and 29% of heterochromatic mark H3K27me3 is found in srHC and euchromatin, respectively. (B) Browser view of srHC and euchromatic fractions compared to H3K9me3 and H3K27me3 histone marks, and mRNA profiles. “DBRs” = differentially bound regions [30]; “srHC + H3K9me3” = H3K9me3 IP performed from srHC fraction. H3K27me3 data are from GSE16368. (C) left: euchromatic fraction and H3K9me3 IP from srHC fraction have been considered for proteomics analysis. Righ: Volcano plot showing 172 significantly identified H3K9me3 heterochromatin proteins (red).

Figure 3. H3K9me3 dynamics during development.

Main events characterizing dynamics of H3K9me3 during pre- and post-implantation, and after gastrulation. Images of zygote, 2-cell, morula and early blastocyst are from https://embryology.med.unsw.edu.au. Profiles of H3K9me3, DNA methylation and gene expression are from [67]. The panel describing dynamics of H3K9me3 and srHC at liver genes during hepatocytes differentiation from uncommitted definitive endodermal cells is form [19].