David Skalnik, Ph.D.
Professor: Department of Pediatrics
Clinical Section: Pediatric Hematology/Oncology
Basic Science Joint Appointment: Biochemistry and Molecular Biology
Postdoctoral Fellowship: The Children's Hospital, Harvard Medical School, Boston, MA
Ph.D.: Stanford University, Stanford, CA, 1987,
Current Research Interests:
Regulation of lineage-specific gene expression in phagocytic blood cells, epigenetics and regulation of chromatin structure during mammalian development.
Research:
My research interests include the study of the "regulatory circuitry" that controls tissue-specific gene expression. Hematopoiesis is a rich system to address this general question, as a large number of lineage-specific genes are induced as blood cells differentiate and acquire specialized properties. As a model system to address this issue, we have analyzing regulation of the Rac2 gene, which is expressed specifically in blood cells. We hav e determined that the chromatin structure of this gene differs in expressing versus non-expressing cells, and that transgenes containing the isolated Rac2 promoter are inappropriately expressed in non-blood cells. Hence, we hypothesize that distant regulatory elements serve to regulate chromatin structure surrounding the Rac2 gene. We have recently demonstrated that expression of a large transgene containing the entire Rac2 gene and 36 kb of upstream flanking sequence is appropriately restricted to blood cells, both in tissue culture cell lines and in transgenic mice. We are currently attempting to identify the precise cis-elements throughout the Rac2 genomic locus that are required to direct this transcriptional specificity.
The second major focus of our lab is the study of the regulation of cytosine methylation, an epigenetic modification important in early mammalian development, genomic imprinting, X-chromosome inactivation, and gene regulation. We have cloned a DNA-binding protein, denoted CpG binding protein (CGBP), which binds DNA sequences containing unmethylated CpG motifs. Disruption of the gene encoding CGBP leads to early embryonic death in mice. We are currently attempting to understand defects in gene regulation and chromatin structure that result from absence of CGBP. This information should help us understand the normal function of CGBP. We are also attempting to study the role of CGBP in the control of post-gasrtrulation development, through the use of conditional gene ablation and anti-sense technologies.
