Maternal expression of the histone demethylase Kdm4a is crucial for pre-implantation development

• Published in: Development (Cambridge) Vol. 144; no. 18; pp. 3264 - 3277
• Main Authors: Sankar, Aditya, Kooistra, Susanne Marije, Gonzalez, Javier Martin, Ohlsson, Claes, Poutanen, Matti, Helin, Kristian
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 15.09.2017
• Subjects: acute myeloid-leukemia; Animals; Blastocysts; Chromatin; colony-stimulating factors; Cytokines - metabolism; Developmental Biology; Embryo Implantation - genetics; Embryo, Mammalian - metabolism; Embryogenesis; Epigenetics; factor-deficient mice; Female; Female fertility; Fertility; Fertilization; Gene Expression Regulation, Developmental; Gene regulation; gene-expression; Genitalia, Female - metabolism; Histone demethylase; Histone Demethylases - metabolism; Histone H3; Histones; human breast-cancer; in-vitro; Infertility, Female - genetics; Infertility, Female - pathology; jmjd2 family; luteinizing-hormone; Lysine; Maternal effect; Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy); Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Mice, Inbred C57BL; Mice, Knockout; null mutation; Oocytes; Post-translation; Pre-implantation development; Pregnancy; Signal Transduction; targeted disruption; Transcription; Uterus; Uterus - metabolism; Zygote - metabolism; Epigenetics; Histone demethylase; Maternal effect; Transcription; Pre-implantation development; Female fertility
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.155473

Regulation of chromatin composition through post-translational modifications of histones contributes to transcriptional regulation and is essential for many cellular processes, including differentiation and development. KDM4A (JMJD2A) is a lysine demethylase with specificity towards di- and tri-methylated lysine 9 and lysine 36 of histone H3 (H3K9me2/me3 and H3K36me2/me3). Here, we report that as a maternal factor plays a key role in embryo survival and is vital for female fertility. female mice ovulate normally with comparable fertilization but poor implantation rates, and cannot support healthy transplanted embryos to term. This is due to a role for Kdm4a in uterine function, where its loss causes reduced expression of key genes involved in ion transport, nutrient supply and cytokine signalling, which impact embryo survival. In addition, a significant proportion of Kdm4a-deficient oocytes displays a poor intrinsic ability to develop into blastocysts. These embryos cannot compete with healthy embryos for implantation , highlighting as a maternal effect gene. Thus, our study dissects an important dual role for maternal Kdm4a in determining faithful early embryonic development and the implantation process.