A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice
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Sendžikaitė, G., Hanna, C., Stewart-Morgan, K., Ivanova, E., & Kelsey, G. (2019). A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice. Nature Communications, 10 (1884)https://doi.org/10.1038/s41467-019-09713-w
DNA methyltransferases (DNMTs) deposit DNA methylation, which regulates gene expression and is essential for mammalian development. Histone post-translational modifications modulate the recruitment and activity of DNMTs. The PWWP domains of DNMT3A and DNMT3B are posited to interact with histone 3 lysine 36 trimethylation (H3K36me3); however, the functionality of this interaction for DNMT3A remains untested in vivo. Here we present a mouse model carrying a D329A point mutation in the DNMT3A PWWP domain. The mutation causes dominant postnatal growth retardation. At the molecular level, it results in progressive DNA hypermethylation across domains marked by H3K27me3 and bivalent chromatin, and developmental regulatory gene de-repression in adult hypothalamus. Evaluation of non-CpG methylation, a marker of de novo methylation activity, further demonstrates the altered recruitment and activity of DNMT3AD329A at bivalent domains. This work provides key molecular insights into the function of the DNMT3A-PWWP domain and the role of DNMT3A in regulating postnatal growth.
Work in G.K.’s lab is supported by grants from the UK Medical Research Council (MR/K011332/1, MR/S000437/1) and Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0423); C.W.H. is supported by a University of Cambridge Centre for Trophoblast Research Next Generation Fellowship; G.S. by an MRC Doctoral Training Programme studentship; and K.R.S.-M. was supported by a scholarship from the Cambridge Overseas Trusts.
External DOI: https://doi.org/10.1038/s41467-019-09713-w
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293723
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/