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DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells.

ABSTRACT: Promoter DNA methylation is a key epigenetic mechanism for stable gene silencing, but is correlated with expression when located in gene bodies. Maintenance and de novo DNA methylation by catalytically active DNA methyltransferases (DNMT1 and DNMT3A/B) require accessory proteins such as UHRF1 and DNMT3L. DNMT3B isoforms are widely expressed, although some do not have active catalytic domains and their expression can be altered during cell development and tumourigenesis, questioning their biological roles. Here, we show that DNMT3B isoforms stimulate gene body methylation and re-methylation after methylation-inhibitor treatment. This occurs independently of the isoforms' catalytic activity, demonstrating a similar functional role to the accessory protein DNMT3L, which is only expressed in undifferentiated cells and recruits DNMT3A to initiate DNA methylation. This unexpected role for DNMT3B suggests that it might substitute for the absent accessory protein DNMT3L to recruit DNMT3A in somatic cells.

SUBMITTER: Duymich CE

PROVIDER: S-EPMC4853477 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells.

Duymich Christopher E CE Charlet Jessica J Yang Xiaojing X Jones Peter A PA Liang Gangning G

Nature communications 20160428

Promoter DNA methylation is a key epigenetic mechanism for stable gene silencing, but is correlated with expression when located in gene bodies. Maintenance and de novo DNA methylation by catalytically active DNA methyltransferases (DNMT1 and DNMT3A/B) require accessory proteins such as UHRF1 and DNMT3L. DNMT3B isoforms are widely expressed, although some do not have active catalytic domains and their expression can be altered during cell development and tumourigenesis, questioning their biologi ...[more]

PMID: 27121154

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Project description:Both DNA methylation and alternative splicing represent mechanisms closely involved in regulation of gene expression and are well known to be involved in cancer susceptibility and development. Human DNA methylation is introduced into DNA by enzymes of the DNA cytosine methyltransferases family, which includes DNMT3B. The DNMT3B protein allows a de novo DNA methylation activity, which is a key mechanism involved in the transformation of normal cell into cancer cell. The DNMT3B3 isoform is overexpressed in cancerous tissues and tumor cell lines, and could act as a dominant negative factor. This isoform was found to be highly expressed in our cohort of non-BRCA1/2 families. Using Infinium Human Methylation 450 BeadChips, we undertook the characterization of the specific methylation profile associated with this DNMT3B3 isoform and its DNMT3B2 wild type counterpart in ER/PR-positive and –negative breast cancer cell lines. A large spectrum of DNMT3B3/DNMT3B2 expression ratio values was observed in cancer and non-cancerous cell lines. Based on their methylation profiles, hierarchical clustering of parental cell lines revealed clustering of cells based on their ER/PR status. Overexpression of DNMT3B3 triggered methylation changes of thousands of CpG sites in MCF7, T-47D, MDA-MB-231 and MCF10A cells. These methylated loci were distributed in similar proportion over the 22 autosomal chromosomes and genomic locations such as promoter, gene body or intergenic regions. Pathways associated with genes containing these differentially methylated CpG sites were also determined regarding their enrichment. Moreover, based on the trend of methylation changes, the results suggest an anti-proliferative effect of the DNMT3B3 isoform through negative effect on its wild-type isoform counterpart DNMT3B2. To our knowledge, this study represents the first exhaustive analysis describing specific methylation profile triggered by modulated expression of DNMT3B isoforms and revealed specific genes and pathways, which could significantly regulate cell growth and proliferation as well as other biological and molecular mechanisms.

Dataset Information

DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells.

Publications

DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells.

Similar Datasets

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