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Skirmantas Kriaucionis’ lab teases apart the contributions of different mechanisms to repress gene expression.

Gene regulation is the important process by which cells control the production level of the protein or RNA encoded by a particular gene to influence many processes such as the development of tissues and organs and responding to environmental triggers. Diseases such as cancer can arise when the regulation of gene expression goes wrong.

Gene expression is a multi-step process, the first step being transcription – the reading of the DNA code and creating an RNA copy. In the cell, DNA is packaged and organised into a structure called chromatin. Control at the level of transcription occurs by opposing activating and repressive factors, which influence the accessibility of chromatin to transcription factors, a diverse group of proteins that can bind the DNA to activate transcription.

Two main mechanisms of gene repression are DNA methylation and histone deacetylation. DNA methylation can repress transcription both directly by altering the binding of transcription factors, and indirectly, by recruiting repressor protein complexes containing histone deacetylases (HDACs). Therefore, one question in this field has been how much of the repressive effect of DNA methylation is due to the downstream activity of HDACs rather than deacetylation-independent effects.

To investigate this question, Martin Cusack and colleagues from Skirmantas Kriaucionis’ lab studied the effect of loss of DNA methylation or histone deacetylation, separately and combined, on chromatin accessibility, transcription factor localisation and gene expression. Through this approach, published in Genome Research, they found that DNA methylation and HDACs function largely independently, although they can act redundantly at 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, which occupy large and relatively inert parts of the genome.

This increased understanding about gene repression has 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 for gene expression, revealing a promising area of therapeutic intervention both on its own and potentially in combination with immunotherapy. Future work aims to reveal how perturbations of these silencing modalities are interpreted in different cancers. 

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