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Epigenetics: how to reach inaccessible genes?

​Biologists have brought to light the operation of "chromatin remodellers", key enzymes in cells. They have discovered how the genetic material, condensed in the nucleus of the cell, needs to be remodelled so that the cell machinery can access the genes. This work, initiated by IBITECS/SBIGeM, coordinated by researchers from a CEA/CNRS/Université Paris-Sud laboratory, under an international collaborative project with Pennsylvania State University (USA) and Guangzhou University (China), was published in Nature on 4 February 2016.​​

Published on 12 April 2017

Our genome, "condensed" into a nucleus of a only a few tens of microns, comprises about 30,000 genes. This compaction is made possible by its organisation as chromatin – "beads on a string" of nucleosomes comprising genomic DNA wound around a protein core. But this nucleosome structure poses numerous problems for the cell, because the DNA is rendered inaccessible to most of the enzymes, in particular the RNA polymerase, responsible for RNA genome transcription, ahead of the protein synthesis necessary for expressing cell identity and function.

This is when the chromatin remodellers come into play. Their function in opening up the chromatin, to make the DNA accessible, was already known, but researchers were unaware of how they worked. In this study, the authors demonstrate that the remodellers bind to precise nucleosomes, situated on either side of the start site (called the promoter) of each gene (see figure). The remodellers work by imposing a constant dynamic on the nucleosomes to which they bind, which play an active role in regulating the genome by allowing recruitment of the enzymes responsible for transcription.

Figure: Analysis of the binding profile of a chromatin remodeller on 12,000 separate genes. The researchers used bioinformatics tools to visualise a large number of genes which were here aligned with their promoter and sorted according to the nucleosome distribution. The presence of the remodeller is shown in dark blue on the nucleosomes (represented by vertical lines) present on either side of the gene start sites. Two distinct nucleosome architectures were thus revealed (top and bottom diagrams). The researchers demonstrated that the activity of the remodellers depends on this nucleosome architecture: some are more specifically required to express genes with a promoter dense in nucleosomes (top), while others act preferentially in a context with a low nucleosomes density (bottom).

© Matthieu Gérard / CEA


Correct gene expression is necessary to define the identity and function of the cells during embryo development and adult life. Fewer than one quarter of the genes are expressed uniformly in all the cells of the organism; the other more specialised genes are necessary and expressed only in certain tissues and certain specific cells. Each cell type is thus faced with the enormous challenge of correctly expressing each of its genes. Numerous cell mechanisms are involved in achieving this goal, with the remodellers taking part by promoting or inhibiting DNA accessibility at the start sites of the genes.

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