Discovery of YL1 protein, deposit chaperone for the histone variant H2A.Z
Crystal structure of human YL1 (colored grey) bound to the H2A.Z/H2B histone pair (red/yellow). Upon YL1 binding, the αC helix of H2A.Z is doubled in length (extension colored in blue).
Nat Struct Mol Biol Apr 2016
March 14, 2016
The team of Ali Hamiche in collaboration with Christophe Romier at the IGBMC, and Stefan Dimitrov (IAL, Grenoble) have discovered and characterized a new pathway for regulation of gene expression. They have showed how a specific histone variant can be deposited into the promoter, for regulating gene expression. Their results were published on March 14, 2016 in the journal Nature Structural & Molecular Biology.
Access to DNA in the cell is tightly controlled and in turn genes can either be silenced, or expressed. This process of turning genes on and off is known as gene regulation. It is important during development. Different sets of genes can be turned on or off in different types of cells, for example to make a muscle cell behave differently than a brain cell. Gene regulation also plays an important role in being able to adapt to rapid environmental changes. Despite of fact that gene regulation is essential to life, their regulation is not yet fully understood.
The gene regulation process
The regulation of genes is intimately related to the organization and function of the chromatin itself. Chromatin is a fundamental structure that is made up of DNA packaged around nucleosomes, and resides in the nucleus of cells. Four histone proteins, H2A, H2B, H3 and H4 form the heart of the nucleosome and are responsible for binding to DNA. Epigenetic mechanisms that can modify the structure and composition of chromatin evolved to help regulate the expression of genes. An important mechanism is the replacement of canonical histones with variant histones to mark special places in the genome. The histone variant H2A.Z is found at the promoters of many genes to regulate their expression, however, how H2A.Z is deposited and removed from the genome is poorly understood.
YL1 protein is a specific chaperone of H2A.Z
The team of Ali Hamiche has probed the epigenetic mechanism to understand how H2A.Z is deposited into chromatin. They identified the YL1 protein as an H2A.Z specific chaperone that deposits H2A.Z into chromatin. In collaboration with the team of Christophe Romier, they solved the structure of YL1 bound to the H2A.Z/H2B dimer. They then identified through mutational analysis how YL1 binds to H2A.Z in a specific manner. Through the combination between biochemical and structural work, researchers demonstrated that YL1 induces a significant structural change in H2A.Z upon binding. However, in contrast to other H2A.Z histone chaperones such as ANP32E, YL1 interacts with H2A.Z much more extensively.
This study has significantly expanded the understanding of the researchers about how H2A.Z is deposited into chromatin and opens a new path to studying other histone chaperones. These results will lead to further studies detailing how the deregulation of the deposition/eviction of histone variants is involved in diseases such as cancer, and thus provides new therapeutic targets.