Resolving mechanisms of gene repression

The first step in the expression of a gene is transcription, in which a strand of DNA is read to generate a mirroring RNA molecule, which can then be read into a protein. The availability of genes for transcription, as well as the initiation, intensity and duration of the process, is tightly regulated and failures at any of those points can cause serious disease, most notably cancer. In a paper published in Genome Research, Martin Cusack and colleagues from Skirmantas Kriaucionis’  lab report their analysis of two key mechanisms that govern the availability of DNA sequences for transcription.

Such regulation occurs primarily though control of access to DNA, which in the nucleus is wound around protein spools and packed into a structure called chromatin. Activating and repressive factors that chemically, or epigenetically, modify chromatin determine how accessible distinct regions of the genome are to the proteins—known as transcription factors—that bind the DNA and initiate the reading of a gene.

DNA methylation and histone deacetylation are two major mechanisms by which gene expression is repressed. The former represses transcription both directly, by altering the binding of transcription factors, and indirectly, by recruiting repressor protein complexes containing histone deacetylases (HDACs). How much of the repressive effect of DNA methylation is due to the downstream activity of HDACs rather than effects independent of deacetylation was an open question.

To find the answer, Martin Cusack and colleagues from Skirmantas Kriaucionis’ lab studied how DNA methylation and histone deacetylation, separately and combined, affects chromatin accessibility, the localization 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. Intriguingly, the study demonstrated that disrupting these two silencing mechanisms together produced elevated occupancy of two transcription factors, YY1 and GABPA, and expression at retrotransposons—a species of “jumping genes”—that occupy large and relatively inert parts of the genome.

Their findings have implications for the design and refinement of therapies targeting cancer cells. The study proposes that combining HDAC inhibitors with DNA methylation inhibitors is more disruptive to gene expression, revealing a promising area of therapeutic intervention. Future work will examine how perturbations of these silencing modalities are interpreted in different cancers.


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