DNMT3B PWWP mutations cause hypermethylation of heterochromatin

Taglini, Francesca and Kafetzopoulos, Ioannis and Rolls, Willow and Musialik, Kamila Irena and Lee, Heng Yang and Zhang, Yujie and Marenda, Mattia and Kerr, Lyndsay and Finan, Hannah and Rubio-Ramon, Cristina and Gautier, Philippe and Wapenaar, Hannah and Kumar, Dhananjay and Davidson-Smith, Hazel and Wills, Jimi and Murphy, Laura C. and Wheeler, Ann and Wilson, Marcus D. and Sproul, Duncan (2024) DNMT3B PWWP mutations cause hypermethylation of heterochromatin. EMBO Reports, 25 (3). pp. 1130-1155. ISSN 1469-3178 (https://doi.org/10.1038/s44319-024-00061-5)

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Abstract

The correct establishment of DNA methylation patterns is vital for mammalian development and is achieved by the de novo DNA methyltransferases DNMT3A and DNMT3B. DNMT3B localises to H3K36me3 at actively transcribing gene bodies via its PWWP domain. It also functions at heterochromatin through an unknown recruitment mechanism. Here, we find that knockout of DNMT3B causes loss of methylation predominantly at H3K9me3-marked heterochromatin and that DNMT3B PWWP domain mutations or deletion result in striking increases of methylation in H3K9me3-marked heterochromatin. Removal of the N-terminal region of DNMT3B affects its ability to methylate H3K9me3-marked regions. This region of DNMT3B directly interacts with HP1α and facilitates the bridging of DNMT3B with H3K9me3-marked nucleosomes in vitro. Our results suggest that DNMT3B is recruited to H3K9me3-marked heterochromatin in a PWWP-independent manner that is facilitated by the protein’s N-terminal region through an interaction with a key heterochromatin protein. More generally, we suggest that DNMT3B plays a role in DNA methylation homeostasis at heterochromatin, a process which is disrupted in cancer, aging and Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome.

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