PREreviews of “DNMT3B PWWP mutations cause hypermethylation of heterochromatin” | PREreview

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DNMT3B PWWP mutations cause hypermethylation of heterochromatin

by Francesca Taglini, Ioannis Kafetzopoulos, Kamila Irena Musialik, Heng Yang Lee, Yujie Zhang, Mattia Marenda, Lyndsay Kerr, Hannah Finan, Cristina Rubio-Ramon, Hannah Wapenaar, Hazel Davidson-Smith, Jimi Wills, Laura C. Murphy, Ann Wheeler, Marcus D. Wilson, and Duncan Sproul

Posted: December 19, 2022
Server: bioRxiv
DOI: 10.1101/2022.12.19.521050

Abstract

The correct establishment of DNA methylation patterns is vital for mammalian development and is achieved largely by thede novoDNA methyltransferases DNMT3A and DNMT3B. Mutations in DNMT3B can cause immunodeficiency-centromeric instability-facial anomalies type 1 (ICF1) syndrome which is characterised by hypomethylated heterochromatin. However, in the genome, DNMT3B primarily localises to actively transcribing gene bodies through the interaction of its PWWP domain with the histone modification H3K36me3 and it is unclear how it is recruited to heterochromatin. Here we show that in DNMT3B knockout cells, loss of DNA methylation predominantly occurs in heterochromatic domains marked by H3K9me3. We also find that PWWP domain mutations which disrupt DNMT3B’s interaction with H3K36me3 result in striking increases of DNA methylation in H3K9me3-marked heterochromatin. Gains of methylation are also observed when the PWWP domain of DNMT3B is deleted. In contrast, we find that the ICF1 syndrome-causing PWWP mutation, S270P, does not result in hypermethylation of heterochromatin and destabilises the protein. We also show that removal of the N-terminus region of DNMT3B affects its recruitment to chromatin and ability to methylate H3K9me3 marked regions. Our results suggest that DNMT3B is recruited to H3K9me3 marked heterochromatin in a PWWP-independent manner and that this recruitment is facilitated by the protein’s N-terminus. More generally, we suggest that DNMT3B plays a role in DNA methylation homeostasis at heterochromatin, a process which is disrupted in ICF syndrome, cancer and aging.

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by Julien Richard Albert

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PREreview by Julien Richard Albert

Authored by Julien Richard Albert

In this manuscript, Taglini and colleagues explore the role of de novo DNA methyltransferase DNMT3B in human heterochromatin methylation. Using a human colorectal cancer cell line lacking DNMT3B, the authors demonstrate a specific loss of DNA methylation over pericentromeric DNA and constitutive…

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