Telephone: (404) 413-5403
Location: 620 Petit Science Center (PSC)
Transcriptional Regulation of the Immune Response
The correct timing of gene expression is vital for normal growth and development. Precise gene transcription is therefore a fundamental process that is regulated in large part by the activities of transcription factors and co-activators. A major mechanism that controls the activity of transcriptional regulators, and thus, transcription itself is post-translational modification. Many changes in gene expression are due to changes in the activity and location of these factors which must interact with other co-activators, co-repressors and the basal transcriptional machinery. Each of these functions is regulated to a great extent by post-translational modifications. It has recently become evident that one such modification, ubiquitination, plays an important role in controlling activator location, activity and abundance through a dynamic partnership with transcription initiation and proteasomal destruction. The long-term goal of my lab is to determine the precise roles of transcription factor ubiquitination in gene regulation.
Though the best known function for ubiquitin is to target proteins for destruction by the 26S proteasome, accumulating evidence suggests that ubiquitination plays a more intricate role in the regulation of gene transcription. The simplest examples of a link between ubiquitin and transcription come from observations that ubiquitin mediated degradation limits the amount of time many activators have to initiate transcription. More recently, studies have demonstrated multiple new roles for ubiquitin in mediating transcription. Ubiquitin has been shown to play a global role in transcription by targeting stalled RNA polymerase II for destruction, thus halting transcription of damaged DNA. More specific roles for ubiquitin in transcription have been shown as well, including controlling activator location and activity by enhancing activator association with other proteins required for transcription of specific genes. It is intriguing to speculate that ubiquitination may promote localization of activators to specific genes for transcription initiation and then conversely that the same modification may target the "retired" activator for destruction by the proteasome. Finally, studies demonstrating association of the 26S proteasome to active promoters give credence to this model and provide an interesting framework on which future studies may be based. Therefore, current research in the lab addresses many of the key questions that remain unanswered as to the role played by the ubiquitin-proteasome system in mediating transcription.
Major histocompatibility complex (MHC) class II molecules play a critical role in immune responses by presenting antigens to CD4 + T lymphocytes. Constitutive and inducible expression of MHC class II molecules on antigen presenting cells is controlled at the level of transcription. Essential for expression of MHC class II is the formation of the multi-protein MHC class II enhanceosome complex consisting of the requisite transcription factors RFX5, CREB and NF-Y. Association of these transcription factors alone however is insufficient to induce MHC class II genes. Instead it is the MHC class II transactivator CIITA that is the master regulator of MHC class II gene transcription. CIITA is not a DNA-binding factor, but functions by interacting with and stabilizing the requisite MHC class II transcription factors at the promoter along with the basal transcription factors TF II D and TF II B to initiate MHC class II transcription.
The lab is focused on CIITA because of its absolute importance in regulating global immune response. The fundamental role of CIITA as a regulator of T cell selection, tolerance induction, antibody production and inflammatory response is underscored by the fact that hereditary loss of CIITA expression, or Bare Lymphocyte Syndrome, results in death in early childhood. As unmodified CIITA is not recruited to the MHC class II enhanceosome, understanding the modifications that lead to CIITA promoter recruitment is essential to potentially regulating the activation of MHC class II genes.