The spreading of facultative H3K9me3-heterochromatin drives congenital disease
Fang-Lin, S.; Chen, W.; Jian-Quan, N.; Wei, Z.; Xue-Lin, C.; Wen-Fei, W.; Yong-Hao, L.; Jian-Feng, C.; Xiao-Bo, G.; Yuan-Ya, J.; Ya-Bin, L.; Xin-YI, L.; Yu-Tong, L.; Kai, L.
Show abstract
Heterochromatin marked by trimethylated histone 3 at lysine 9 (H3K9me3) plays fundamental roles in reprogramming to direct cell fate determination in higher eukaryotes. However, the upstream factors that guide the establishment and spreading of H3K9me3-heterochromatin, leading to human developmental malformations, remain elusive. In this study, we found that Cdk13, a member of RNA polymerase II (RNAPII) kinase, suppresses congenital heart syndrome by preventing global facultative H3K9me3-heterochromatin spreading. Additionally, Cdk13 directs the phosphorylation of a large set of heterochromatin proteins at specific sites, which are required for the interaction between HP1 and histone H3K9 methyltransferases. Furthermore, we identified a compound, an inhibitor of heterochromatin regulators, that can alleviate syndromic heart defects in Cdk13-mutant mice through the inhibition of H3K9me3-heterochromatin spreading. In summary, this study reveals a novel role and mechanism of Cdk13-triggered facultative H3K9me3-heterochromatin spreading in human genetic disease and paves the way for the treatment of congenital heart syndrome.
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