LSH and G9a/GLP complex are required for developmentally programmed DNA methylation

Abstract

LSH, a member of the SNF2 family of chromatin remodeling ATPases encoded by the Hells gene, is essential for normal levels of DNA methylation in the mammalian genome. While the role of LSH in the methylation of repetitive DNA sequences is well characterized, its contribution to the regulation of DNA methylation and the expression of proteincoding genes has not been studied in detail. In this report we investigate genome-wide patterns of DNA methylation at gene promoters in Hells -/-mouse embryonic fibroblasts (MEFs). We find that in the absence of LSH, DNA methylation is lost or significantly reduced at~20% of all normally methylated promoter sequences. As a consequence, a large number of genes are misexpressed in Hells -/-MEFs. Comparison of Hells -/-MEFs with wild-type MEFs and embryonic stem (ES) cells suggests that LSH is important for de novo DNA methylation events that accompany the establishment and differentiation of embryonic lineage cells. We further show that the generation of normal DNA methylation patterns and stable gene silencing at specific promoters require cooperation between LSH and the G9a/GLP complex of histone methylases. At such loci, G9a recruitment is compromised when LSH is absent or greatly reduced. Taken together, our data suggest a mechanism whereby LSH promotes binding of DNA methyltransferases and the G9a/GLP complex to specific loci and facilitates developmentally programmed DNA methylation and stable gene silencing during lineage commitment and differentiation.

A replication-dependent passive mechanism modulates DNA demethylation in mouse primordial germ cells

“…Changes in H3K9 methylation in SINEs and LINE-1 in developing PGCs are similar to those in Glp KO ESCs, which suggests that active repression of GLP expression triggers global H3K9 demethylation in developing PGCs. G9a is an essential partner of GLP in the H3K9 methylation complex, and it is required for the maintenance in ESCs of DNA methylation in the promoter regions of germline-specific genes and the Rhox gene cluster, which are expressed in developing PGCs (Daggag et al, 2008;Dong et al, 2008;Myant et al, 2011). Considering these findings, we speculate that the repression of GLP expression establishes the primed state of transcription of germline-specific genes in developing PGCs, allowing germ cells derived from PGCs to fully activate germlinespecific genes during further differentiation.…”

Lysine methyltransferase G9a is required for de novo DNA methylation and the establishment, but not the maintenance, of proviral silencing

“…Interestingly, the chromatin remodeler LSH interacts with G9a to establish the silencing of many genes in mESCs (50). Because LSH is also required for the silencing of retrotransposons, G9a may establish proviral silencing in a pathway that also involves chromatin remodeling.…”

RAF-MEK-MAPK Pathway Targeted by Tumor Suppression and Anticancer Therapeutic Agents

“…Mechanistically, together with histone methyltransferase G9a, LSH is critical for the normal development of mammals and is involved in the establishment and maintenance of DNA methylation [36]. Since apart from depositing of H3K9me2 [37], G9a and its partner modifier GLP also interact with DNA methyltransferases (DNMTs) and protect proper DNA methylation at certain loci [38], LSH might also directly interact with DNMTs and affect the patterns of DNA methylation in the cells.…”