Developmental gene expression profiles are precisely regulated by lineage-defining transcription factors that utilize both epigenetic and classical transactivation mechanisms to regulate their target genes. The T-box transcription factor family plays essential roles in numerous developmental systems, ranging from early embryogenesis into the adult. The dysregulation of the T-box family leads to several human genetic diseases, including immunodeficiencies, cancer, congenital heart defects, limb abnormalities, cleft palate, and pituitary deficiencies. In the immune system, two T-box factors, T-bet and Eomesodermin, have been shown to play critical roles in the development and functioning of both adaptive and innate immune cells. Genetic studies have shown that the loss of either T-bet, or a combination of T-bet and Eomesodermin, results in higher susceptibility to infectious diseases as well as alterations in the incidence for autoimmune conditions. In my laboratory, we study the mechanisms by which the T-box family establishes developmentally appropriate gene expression networks, with a special emphasis on understanding T-bet’s role in regulating gene networks in diverse immune cell types.
Our previous studies have demonstrated that T-box factors require both a family member specific transactivation potential and a conserved ability to recruit histone modifying activities to properly function at select target genes during cellular differentiation. Significantly, the T-box DNA binding domain, the defining feature for the T-box family, physically and functionally interacts with both H3K27-demethylase and H3K4-methyltransferase activities. These interactions are required for the ability of diverse T-box family members to establish gene networks in development, as noted by the numerous human genetic disease mutations specifically disrupting these activities. Current research in the lab is focused on understanding the context in which the T-box family utilizes the common epigenetic activities as well as the family member specific transactivation potential to regulate gene expression at both the global and individual target gene level. Importantly, examining these questions in T helper cell differentiation in the immune system provides a valuable model system to define the molecular requirements for establishing developmental gene networks.
