KMT1E Mediated H3K9 Methylation Is Required for the Maintenance of Embryonic Stem Cells by Repressing Trophectoderm Differentiation

Abstract

Dynamic regulation of histone methylation by methyltransferases and demethylases plays a central role in regulating the fate of embryonic stem (ES) cells. The histone H3K9 methyltransferase KMT1E, formerly known as ESET or Setdb1, is essential to embryonic development as the ablation of the Setdb1 gene results in peri-implantation lethality and prevents the propagation of ES cells. However, Setdb1-null blastocysts do not display global changes in H3K9 methylation or DNA methylation, arguing against a genome-wide defect. Here we show that conditional deletion of the Setdb1 gene in ES cells results in the upregulation of lineage differentiation markers, especially trophectoderm-specific factors, similar to effects observed upon loss of Oct3/4 expression in ES cells. We demonstrate that KMT1E deficiency in ES cells leads to a decrease in histone H3K9 methylation at and derepression of trophoblast-associated genes such as Cdx2. Furthermore, we find genes that are derepressed upon Setdb1 deletion to overlap with known targets of polycomb mediated repression, suggesting that KMT1E mediated H3K9 methylation acts in concert with polycomb controlled H3K27 methylation. Our studies thus demonstrate an essential role for KMT1E in the control of developmentally regulated gene expression programs in ES cells.

The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryos

“…In our study, however, Cdc14b was not differentially expressed between Setdb1-deficient and control GV oocytes as determined by RNA sequencing analyses. This finding is surprising as both laboratories studied the same conditional deletion allele of Setdb1 (Lohmann et al, 2010), yet on slightly different genetic backgrounds (C57Bl/6-129Sv hybrid versus C57Bl/6J). Moreover, in contrast to Kim et al (2016), we did not perform hormonal superovulation in any of the experiments dealing with oocyte maturation.…”

“…Mice maternally deficient for Setdb1 were generated by crossing Setdb1 f/f mice (Lohmann et al, 2010) with Zp3-cre transgenic mice to induce deletion in growing oocytes. Mice were maintained on a C57Bl/6J genetic background.…”

“…Setdb1 is able to mono-, di-and tri-methylate H3K9 (Loyola et al, 2009;Wang et al, 2003). Setdb1 is essential for pluripotency maintenance and repression of trophectodermal differentiation in embryonic stem cells (ESCs) (Lohmann et al, 2010;Yeap et al, 2009;Yuan et al, 2009), and for primordial germ cell (PGC) and neuronal progenitor development (Tan et al, 2012). Moreover, in these cells Setdb1 is required for H3K9me3 deposition at and transcriptional silencing of endogenous long terminal repeat (LTR)-containing retroviruses (ERVs) such as those belonging to the ERV1 (class I) and ERVK [class II; including intracisternal A-type particle (IAP) and early transposons (ETn/MusD)] repeat families.…”

Embryonic stem cell and induced pluripotent stem cell: an epigenetic perspective

“…ESCs lacking Kmt1e (also called Setdb1 or Eset), an H3K9-specific HMT, fail to self-renew while acquiring trophectoderm properties [75][76][77][78]. Consistent with its role in ESCs, depletion of Kmt1e reduces the reprogramming efficiency in iPSCs generation [74].…”

SETDB1 modulates PRC2 activity at developmental genes independently of H3K9 trimethylation in mouse ES cells

“…Consistently, we have shown previously that Setdb1 is essential for embryogenesis (Dodge et al 2004). In coordination with POU5F1, SETDB1 suppresses the trophectoderm cell lineage (Yuan et al 2009;Lohmann et al 2010). SETDB1 was also shown to be involved in various developmental processes (Wang et al 2011;Mysliwiec et al 2012) as well as silencing of endogenous retrovirus (Matsui et al 2010;Karimi et al 2011).…”