Joseph D. Fontes, Ph.D.

I am interested in how gene transcription is regulated during development and disease and how the mechanisms of regulation might be manipulated as a therapeutic strategy. My laboratory studies the transcriptional regulation of major histocompatibility complex class II (MHC II) genes. MHC II proteins present peptide antigen to CD4+ T cells, and as such these proteins are critical in the normal and pathological functioning of the immune system.

We study the protein factors that bind to MHC II promoters and activate their transcription. The class II trans-activator (CIITA) is known as the “master switch” for MHC II transcription, as all other factors requires for MHC II transcription are present in most cell types and it is the developmental or induced expression of CIITA that is necessary for the transcription MHC II genes. We and others have shown that CIITA mediates the recruitment of chromatin modifying factors as part of its mechanism of action. Studying the role of CIITA in modifying chromatin structure is one ongoing interest of my lab.

Recently, we have identified a new family of transcription factors that associate with CIITA and regulate MHC II gene transcription. This family is the zinc finger X-linked duplicated (ZXD) genes, of which there are three members: ZXDA, ZXDB and ZXDC. These proteins have ten zinc fingers and we have shown that ZXDA and ZXDC have potent transcriptional activation domains. We found that ZXDA and ZXDC heterodimerize and associate with CIITA, and through an as yet unknown mechanism, promote the transcription of MHC II genes. ZXDC is associated with MHC II gene promoters prior to and after the induction of MHC II transcription. Our current work focuses on the ZXD gene family, how they regulate transcription and their role beyond MHC II gene transcription.

MHC class II promoters consist of conserved upstream elements known as the W (or S box), X1, X2 and Y boxes. The complexes that bind the X1 and Y boxes are the heterotrimeric RFX and NFY complexes, respectively. The CREB protein binds the X2 box. These factors serve as a “docking site” for CIITA. A complex of ZXDA and ZXDC interacts with CIITA, but is also present at MHC II promoters in the absence of CIITA, though its binding site is not currently known.

Representative Publications