Subtleties of repression

One important way in which cells regulate gene expression is by managing access to DNA, which is wound around protein spools and packed into a structure called chromatin. Accessibility enables interaction with regulatory molecules and the enzymes that transcribe genes. Numerous chemical, or epigenetic, modifications to chromatin are known to alter its structure to govern access, but how they collaborate functionally has been a puzzle. In a September paper in Genome Research, a team led by Ludwig Oxford’s Skirmantas Kriaucionis reported the analysis of two epigenetic mechanisms—DNA methylation and histone deacetylation—of gene repression. The former acts both directly, by altering the binding of transcription factors, which initiate the reading of genes, and indirectly, by recruiting repressor protein complexes containing histone deacetylases (HDACs). Both processes are targets for cancer therapies. Yet it has been unclear how much of the repressive effect of DNA methylation is due to the downstream activity of HDACs rather than effects independent of deacetylation. To find out, the researchers studied how the two epigenetic events affect chromatin accessibility, the occupancy of transcription factors and gene expression. They report that DNA methylation and HDACs function largely independently, although they can act redundantly on some regions of the genome. This suggests combining HDAC inhibitors with DNA methylation inhibitors might be an effective strategy for cancer therapy.

This article appeared in the December 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).


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