X-linked H3K27me3 demethylase Utx is required for embryonic development in a sex-specific manner

Abstract

Embryogenesis requires the timely and coordinated activation of developmental regulators. It has been suggested that the recently discovered class of histone demethylases (UTX and JMJD3) that specifically target the repressive H3K27me3 modification play an important role in the activation of "bivalent" genes in response to specific developmental cues. To determine the requirements for UTX in pluripotency and development, we have generated Utxnull ES cells and mutant mice. The loss of UTX had a profound effect during embryogenesis. Utx-null embryos had reduced somite counts, neural tube closure defects and heart malformation that presented between E9.5 and E13.5. Unexpectedly, homozygous mutant female embryos were more severely affected than hemizygous mutant male embryos. In fact, we observed the survival of a subset of UTX-deficient males that were smaller in size and had reduced lifespan. Interestingly, these animals were fertile with normal spermatogenesis. Consistent with a midgestation lethality, UTX-null male and female ES cells gave rise to all three germ layers in teratoma assays, though sex-specific differences could be observed in the activation of developmental regulators in embryoid body assays. Lastly, ChIP-seq analysis revealed an increase in H3K27me3 in Utx-null male ES cells. In summary, our data demonstrate sex-specific requirements for this X-linked gene while suggesting a role for UTY during development.KDM6A | polycomb

UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia

“…UTX (also called KDM6A) is a Jumonji C domain-containing demethylase that removes the repressive histone mark trimethylated histone 3 Lys27 (H3K27me3) (Agger et al 2007;Hong et al 2007). Previous studies have shown that UTX plays important roles in embryonic development Welstead et al 2012) and adult hematopoiesis (Thieme et al 2013). Our identification of an interaction between TAL1 and UTX ( Fig.…”

Resetting the epigenome for heart regeneration.

“…Moreover, UTX deletion results in failure of ESCs to differentiate into the cardiac lineage [92,93]. Similarly, Jmjd3 knockout ESCs fail to differentiate into mesoderm and cardiac lineages [94].…”

“…Similarly, Jmjd3 knockout ESCs fail to differentiate into mesoderm and cardiac lineages [94]. Global genetic deletion of Utx results in embryonic lethality by E13.5 with developmental abnormalities in cardiac chamber formation [92,93]. Jmjd3 homozygous knockout mice die before E6.5 [94].…”

DNA methylation and chromatin dynamics during postnatal cardiomyocyte maturation

“…Studies have shown that Utx histone demethylase function is directed by core cardiac specific TFs, such as Nkx2.5, Gata4 and Tbx5, to the enhancer regions of cardiac genes, which leads to the transcriptional activation of their target genes during cardiac differentiation (Lee et al, 2012). Moreover, Utx deletion results in failure of ESCs to differentiate into the cardiac lineage (Lee et al, 2012;Welstead et al, 2012). Similarly, Jmjd3 knockout ESCs fail to differentiate into mesoderm and cardiac lineages (Ohtani et al, 2013).…”

“…Utx results in embryonic lethality by E13.5 with developmental abnormalities in cardiac chamber formation (Lee et al, 2012;Welstead et al, 2012). Jmjd3 homozygous knockout mice die before E6.5 (Ohtani et al, 2013).…”