DNMT3B PWWP mutations cause hypermethylation of heterochromatin

• Published in: EMBO reports Vol. 25; no. 3; pp. 1130 - 1155
• Main Authors: Taglini, Francesca, Kafetzopoulos, Ioannis, Rolls, Willow, Musialik, Kamila Irena, Lee, Heng Yang, Zhang, Yujie, Marenda, Mattia, Kerr, Lyndsay, Finan, Hannah, Rubio-Ramon, Cristina, Gautier, Philippe, Wapenaar, Hannah, Kumar, Dhananjay, Davidson-Smith, Hazel, Wills, Jimi, Murphy, Laura C, Wheeler, Ann, Wilson, Marcus D, Sproul, Duncan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-03-2024
• Subjects: Biomedical and Life Sciences; EMBO09; Life Sciences; Epigenetics; DNA Methylation; Heterochromatin
• ISSN: 1469-3178; 1469-221X; 1469-3178
• DOI: 10.1038/s44319-024-00061-5

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.
Synopsis
The DNA methyltransferase DNMT3B is recruited to gene bodies through its PWWP domain’s interaction with H3K36me3. This study shows DNMT3B PWWP mutations cause hypermethylation of H3K9me3-marked heterochromatin facilitated by DNMT3B’s N-terminal region.
Removal of DNMT3B results in losses of DNA methylation from H3K9me3-methylated heterochromatin.
Mutation or deletion of DNMT3B’s PWWP domain results in the hypermethylation of H3K9me3-marked heterochromatin.
Recruitment of DNMT3B to H3K9me3 is facilitated by its N-terminal region, which interacts with HP1α.
The DNA methyltransferase DNMT3B is recruited to gene bodies through its PWWP domain’s interaction with H3K36me3. This study shows DNMT3B PWWP mutations cause hypermethylation of H3K9me3-marked heterochromatin facilitated by DNMT3B’s N-terminal region.