My research seeks to understand the functional mechanism of action through which novel cis-elements control human major histocompatibility complex class II (MHC-II) gene expression, and to identify protein components required for the function of these cis-elements. MHC-II gene expression is tissue-specific, and is regulated both developmentally and by the actions of immune cytokines. Proper expression of the MHC-II genes is important for the maintenance of a healthy and active adaptive immune system. Failure to properly regulate MHC-II results in a defective immune system and can lead to many disorders including autoimmune diseases, infectious diseases and cancers.
Transcription factors and cis-elements such as enhancers and promoters are critical features involved in gene expression. Recent genetic evidence has established that insulators also represent a mechanism for gene regulation, especially within complex genetic loci. As gene regulatory elements, insulators have two distinct functions: blocking enhancers when placed between an enhancer and a gene; and protecting the gene from being silenced by adjacent heterochromatin when flanking a gene. To date, I have focused on how insulators or chromatin boundary elements function in MHC-II and immune system gene expression using human cell lines as well as mouse model systems.
CCCTC-binding factor, CTCF, is required for the function of all known mammalian insulators. I have previously mapped CTCF binding sites throughout the human and mouse MHC-II locus. My research established that CTCF is involved in demarcating the boundaries of interacting foci and looping structures that rearrange the MHCII locus in the presence of class II transactivator, CIITA (master regulator of MHC-II). To further our mechanistic understanding of MHC-II insulators we are generating deletions of CTCF bound-cis-elements in mice. These studies will provide a direct in vivo role for CTCF and genome organization in MHC-II gene expression and the adaptive immune system.