In order to understand better how TFII-I family transcription factors regulate nuclear gene expression in response to external stimuli, we have currently undertaken three projects and ask the following questions:


How does TFII-I mediate growth factor signaling to control cellular proliferation?

In this project we are addressing how might TFII-I be tethered to the cytoplasm and how does it gets released in response to growth factor signaling. Moreover, we are working towards gaining a mechanistic insight as to how TFII-I may control regulation of pro-proliferative c-fos gene on one hand and anti-apoptotic gene Bclx on the other. We believe that part of this answer lie in the fact that TFII-I has multiple alternatively spliced isoforms, which has distinct subcellular localization and carry out distinct function in response to growth factors. We are using isoform specific reagents to address the function of these TFII-I isoforms. Furthermore, we are interested in deciphering a potential role for TFII-I in cell cycle control since it appears to control the transcriptional activity of cyclin D1.
     

How does TFII-I associate with the PML bodies and how does this alter the transcription function of TFII-I?

We have observed that once TFII-I translocates to the nucleus, it associates with the pro myelocytic leukemia (PML) bodies. TFII-I also associates with histone modifying (HDAC) and SUMOylating enzymes and the transcriptional outcome is fundamentally different depending on which enzyme it associates with. Because these enzymes are also components of the PML bodies, we postulate that association of TFII-I with the PML bodies might shape its ultimate transcription functions.

How does TFII-I function in response to antigenic signaling in B cells?

We have shown that TFII-I physically and functionally interacts with Bruton’s tyrosine kinase that is necessary for proper B cell function. We continue to decipher the BTK-TFII-I pathway by generating TFII-I transgenic mouse model and generating siRNA-mediated TFII-I knockdown in B cells. We are also addressing the role of TFII-I family member, BEN in B cell differentiation and immune function.

 

How do TFII-I family members play a role in Williams-Beuren Syndrome?

Recently, we have also initiated a project to understand the role of TFII-I family of transcription factors in Williams-Beuren Syndrome Williams-Beuren Syndrome (WBS) is a rare developmental disorder that is caused by a hemizygous microdeletion of approximately 1.5 MB, spanning 17 genes at chromosomal location 7q11.23. However, we lack a complete understanding of molecular basis for WBS. Although this multisystem dysfunction with unusual craniofacial, behavioral and cognitive features occurs most likely due to haplo-insufficiency of several genes, rare cases with much smaller deletions have provided clues to identifying specific genes that may be causal to distinctive physical and cognitive defects. Two of these genes, GTF2I and GTF2IRD1 encode the TFII-I family of transcription factors. TFII-I and its relative MusTRD1/BEN exhibit extensive and overlapping expression patterns in a variety of tissues during mouse pre- and post-implantation development, suggesting a functional role for these proteins in early development. These proteins are also abundantly expressed in the hippocampus, a portion of the brain that plays a role in learning and memory, further indicating that they may be causal to some WBS traits. We wish to better understand the role of these factors in WBS.