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A histone variant at the heart of a new mechanism of gene regulation

The binding of ANP32E to H2A.Z (red) induces a significant conformational change of the helix αC of H2A.Z whose length is doubled (purple). This change has a major effect in destabilizing the binding of H2A.Z to the H3/H4 (blue/yellow) histone pair within the nucleosome, most likely causing the eviction of the H2A.Z/H2B pair from chromatin.

ANP32E is a histone chaperone that removes H2A.Z from chromatin.

Obri A(1), Ouararhni K(1), Papin C(1), Diebold ML(2), Padmanabhan K(3), Marek M(2), Stoll I(4), Roy L(4), Reilly PT(5), Mak TW(6), Dimitrov S(3), Romier C(2), Hamiche A(4).

Nature Jan. 30, 2014


Jan. 22, 2014

The team of Dr. Ali HAMICHE (IGBMC), in collaboration with Drs. Christophe ROMIER (IGBMC), Stefan Dimitrov (IAL, Grenoble) and Tak MAK (UHN, Toronto, Canada) has identified a new mechanism of regulation of gene expression. This is the first example showing at a molecular level the relief of the inhibition of a promoter through a specific histone removal. Their results are published on January 22nd in the journal Nature.

 

Each cell expresses, or turns on, only a fraction of its genes. The rest of the genes are repressed, or turned off. The process of turning genes on and off is known as gene regulation. Gene regulation is an important part of normal development. Genes are turned on and off in different patterns during development to make a brain cell look and act different from a liver cell or a muscle cell, for example. Gene regulation also allows cells to react quickly to changes in their environments. Although we know that the regulation of genes is critical for life, this complex process is not yet fully understood.

 

Gene regulation is closely linked to the organization and function of chromatin, a fundamental structure of life formed of nucleosomes that package the DNA inside the nucleus of our cells. The heart of the nucleosome consists of an assembly of four proteins called histones (H2A, H2B, H3 and H4) that bind DNA. Intricate processes, called epigenetic mechanisms, have evolved to help change the chromatin in response to environmental signals, thereby modifying the expression of genes. Among these epigenetic mechanisms, the replacement of the canonical histones by histone variants in nucleosomes is known to be very important, but is still poorly understood in molecular terms. Among the histone variants, H2A.Z is found mostly on the promoters of active genes, but how it is deposited and removed from these locations is not understood.

 

The team of Ali Hamiche by using a multidisciplinary approach is dedicated to the understanding of the precise role of H2A.Z in the activation/inactivation of genes. They identified the protein ANP32E as a specific “chaperone“ of the histone variant H2A.Z. Through a fruitful collaboration with other research group, the Hamiche’s team has demonstrated that ANP32E plays a role in the eviction of H2A.Z prior to gene activation. The combination of structural and biochemical approaches has shown that binding of ANP32E to H2A.Z leads to an important structural change in H2A.Z, causing destabilization of the H2A.Z/H2B complex within the nucleosome, thus promoting the eviction of this complex from the nucleosome. Furthermore, they showed that in mice lacking ANP32E H2A.Z accumulated on promoters and was redistributed on other sequences in the regulation of gene expression. These results are in agreement with the literature showing a deregulation of ANP32E expression in various human tumors.

 

This work is essential since it is the first time that a mechanism of histone eviction is highlighted in molecular terms and correlated with results spanning the full genome. These findings open the way to the deciphering of how other histones are deposited and evicted from chromatin. This in turn should give a strong impetus to the understanding of how the deregulation of the deposition/eviction of histone variants can lead to diseases, further paving the way to the development of new therapeutic approaches.

 

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