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.

doi:10.1101/2023.08.11.552907

bioRxiv · 10.1101/2023.08.11.552907

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.

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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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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.. 2023-08-14. The spreading of facultative H3K9me3-heterochromatin drives congenital disease. https://doi.org/10.1101/2023.08.11.552907

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