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Identification of a new partnership in gene expression regulation

On the left, compact chromatin. On the right, decondensed chromatin following the interaction of mutated TFIIH with the GCN5 enzyme.

March 20, 2019

Patients with a combined form of xeroderma pigmentosum and Cockayne syndrome have a wide range of clinical characteristics, including photosensitivity of the skin, predisposition to cancer and developmental disorders. At the origin of this rare genetic disease, a mutation of a subunit of the gene encoding TFIIH that plays a key role both in gene transcription and in gene repair. By studying patients' cells, researchers from Frédéric Coin's team at the IGBMC (CNRS/Inserm/Unistra) showed that the interaction of the TFIIH complex with the GCN5 enzyme leads to an increase in the enzymatic activity of GCN5, resulting in an uncontrolled remodelling of the chromatin and an overexpression of a large number of genes that may cause certain symptoms in patients.These results are published on March 20, 2019 in the journal Nature Communication.

 

In eukaryotic cells, the genetic material is organized into a complex structure of DNA and proteins called chromatin. Its configuration, which can be condensed or decondensed, impacts gene expression. By studying the cells of patients with both xeroderma pigmentosum and Cockayne syndrome, Frédéric Coin's team observed that the interaction of the TFIIH factor from patient’s cells with the GCN5 enzyme leads to the decondensation of chromatin and the overexpression of a large number of genes. The researchers then showed that by inhibiting the action of the GCN5 enzyme, chromatin returned to its compact form and genes were no longer overexpressed. This work suggests that the action of drugs inhibiting GCN5 could be used to treat patients with these rare genetic diseases.

 

The researchers also observed that a number of overexpressed genes in these patients were also overexpressed in patients with Cockayne syndrome alone due to mutations in other genes, showing that there may be a transcriptional signature associated with this disease. Such a signature would improve the diagnosis of Cockayne's syndrome.

 

In addition, since TFIIH and GCN5 are also involved in cancer, the deregulation of the TFIIH/GCN5 interaction observed in these patients could in some cases also be the cause of excessive proliferation of tumor cells.

 

This research establishes the key role of the interaction between the TFIIH factor and the GCN5 enzyme in the regulation of chromatin and gene expression, paving the way for new diagnostic and therapeutic approaches for the treatment of genetic diseases and rare cancers in which TFIIH is mutated.

 

This study was funded by the ANR, the ARC Foundation, the European Research Council, France Genomics, the Foundation for Medical Research and the Scientific and Technological Research Council of Turkey.

 

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