title: 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 Utx-null 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.
authors: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
authors: G Grant
authors: GG
authors: Welstead
authors: Menno P
authors: MP
authors: Creyghton
authors: Steve
authors: S
authors: Bilodeau
authors: Albert W
authors: AW
authors: Cheng
authors: Styliani
authors: S
authors: Markoulaki
authors: Richard A
authors: RA
authors: Young
authors: Rudolf
authors: R
authors: Jaenisch
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D055786:Gene Knockout Techniques; D056466:Histone Demethylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D012737:Sex Factors
chemical_list: D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C111778:Utx protein, mouse; C523761:Kdm6b protein, mouse