Chromatin structure and the control of gene expression
Dr. Wu studies the role of chromatin structure and remodeling in gene transcription — areas that are central to understanding how genomic information is selectively programmed for expression in the development of organisms. His laboratory is best known for the discoveries of DNAse I hypersensitivity at eukaryotic promoters, of the Heat Shock Transcription Factor - master regulator of the cellular stress response, and of ATP-dependent chromatin remodeling enzymes. At Janelia Farm and NCI, Wu is extending his work in new directions, to developing fresh analytical methods for the epigenome, and imaging local chromatin dynamics and large-scale chromatin folding in live cells.
The Wu laboratory investigates the biochemical basis for histone H2A.Z exchange using the budding yeast model organism. They 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. His laboratory is continuing studies to elucidate molecular details of the mechanism of histone H2A.Z replacement.
The page was last updated on Thursday, April 2, 2015 - 10:24am