Wednesday Afternoon Lecture Series

Annual George Khoury Lecture

The organization of eukaryotic genomes in chromatin dynamically regulates the access of chromosomal proteins to DNA and provides a general mechanism for the control of genome activities. Nucleosomes are the primary units of chromatin, consisting of 147 bp of DNA wrapped around an octameric core of histones H2A, H2B, H3, and H4. While most nucleosomes contain so-called canonical histones that comprise the bulk of eukaryotic chromatin, there exist nonallelic, variant histones that mark genomic regions with special functions. The conserved histone variant H2A.Z is part of a universal chromatin architecture created at promoters and enhancers genome-wide, from yeast to human. H2A.Z is important for critical chromosome activities, including gene expression and DNA repair. In humans, H2A.Z controls the expression of developmental and cell cycle regulators, and H2A.Z overexpression is associated with cancer progression. These functions of histone H2A.Z appear to be linked to the increased dynamics of H2A.Z-containing nucleosomes.

The Wu laboratory investigates the biochemical basis for histone H2A.Z exchange using the budding yeast model organism. We have identified the yeast SWR1 ATP-dependent chromatin remodeling complex as the responsible enzyme. In a purified system, SWR1 removes H2A-H2B dimers from nucleosomes and deposits free H2A.Z-H2B dimers in an ATP-dependent manner. Homologous enzymes have since been characterized in mammalian systems. How does SWR1 recognize promoters and enhancers genome-wide? Recently, they found that recognition of DNase hypersensitive, nucleosome-free DNA is the dominant mechanism over histone acetylation in targeting SWR1 to promoters globally. Such 'hierarchical cooperation' between DNA and histone signals may provide a general model that unites classical gene regulation by DNA-binding factors with ATP-dependent nucleosome remodeling and post-translational histone modifications. Once targeted to promoters, SWR1 activation requires further recognition of both the canonical nucleosome and the H2A.Z-H2B dimer, a process that assures self-termination of the exchange reaction. The Wu lab is continuing studies to elucidate molecular details of the mechanism of histone H2A.Z replacement.

For more information go to http://wals.od.nih.gov/