Combined loss of Jmjd1a and Jmjd1b reveals critical roles for H3K9 demethylation in the maintenance of embryonic stem cells and early embryogenesis

H3K9 methylation is unevenly distributed in mammalian chromosomes. However, molecular mechanism controlling the uneven distribution and its biological significance remain to be elucidated. Here we show that Jmjd1a and Jmjd1b selectively target H3K9 demethylation of gene-dense regions of chromosomes, thereby establishing H3K9 hypomethylation state in euchromatin. Combined loss of Jmjd1a and Jmjd1b caused perturbed expression of metabolic genes and rapid cell death in embryonic stem (ES) cells. Furthermore, Jmjd1a/Jmjd1b-deficient embryos died soon after implantation accompanying epiblast cell death. These results indicate that Jmjd1a/Jmjd1b-meditated H3K9 demethylation has critical roles for ES cell maintenance and early embryogenesis. Finally, genetic rescue experiments clarified that H3K9 overmethylation by G9a was the cause of the cell death and perturbed gene expression of Jmjd1a/Jmjd1b-depleted ES cells. We summarized that Jmjd1a and Jmjd1b, in combination, ensure ES cell viability and early embryogenesis by establishing the correct H3K9 methylated epigenome.