Molecular Basis of Genome Organization

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Areas of Investigation
Genes in a cell are organized like clothes in a closet. Similar kinds are grouped together; types that are used often are separated from those not currently needed. This organization even changes in response to external stimuli. In the summer, shorts and T-shirts are in an accessible drawer while hats and scarves are tucked in a box in the back. Indeed, our cells use different genes in response to temperature, aging, and illness. Our lab is interested in understanding the molecular basis of genome organization: How are drawers formed in a cell? What proteins act as boxes for DNA?

Ubiquitous long-range interactions fold genomes into defined conformations. The CCCTC-binding factor (CTCF) has repeatedly emerged as a necessary component for the formation of loops that bridge distal DNA elements on the same and even different chromosomes to regulate transcription. ~10,000 binding sites localize mostly to intergenic regions, but also to introns, promoters, and exons. This dynamic and regulated genome organization is one of the large-scale cellular phenomena now becoming amenable to atomic resolution mechanistic understanding through the concerted efforts of genetics, biochemistry, and structural biology.

Significance
Our laboratory studies the genome organization of human viruses associated with cancer. Our long-term goal is to understand the structure-function mechanisms that couple genome organization and transcriptional regulation. We have chosen to examine viruses as our systems of interest not only because of relevance to human disease, but also because viral genomes, unlike human chromosomes, are genetically tractable and well annotated.

Approaches
We are a multidisciplinary group that combines structural and biochemical methods with genetic and cellular assays. We study the Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus, human immunodeficiency virus, and human papillomavirus.

Contributions

  1. Defined the molecular architecture of the CTCF family of proteins
  2. Identified at high resolution the occupancy of CTCF and other organizers in the genomes of herpesviruses

Questions addressed in ongoing studies

  1. What is the structure of CTCF and chromatin loops?
  2. What is the function of organizing proteins on the Epstein-Barr virus genome?
  3. Does CTCF organize the genomes of the Kaposi’s sarcoma associated herpesvirus, human immunodeficiency virus, and human papillomavirus?