Dr. Wenzheng Zhang
The University of Texas Health Science Center at Houston
Department of Internal Medicine - Renal Diseases and Hypertension
- Regulation of gene expression
- Renal development and function
- Action of steroid hormones; tumorigenesis
Histones are subject to extensive posttranslational modifications including methylation. Histone H3 lysine 79 methylation is catalyzed by members of Dot1 methyltransferase family. We have reported 5 alternative splicing variants (Dot1a-e) generated by mouse Dot1 gene. One of my research interests is the function of Dot1a in the steroid hormone aldosterone signaling pathway. Aldosterone plays a major role in the regulation of salt balance and the pathophysiology of cardiovascular and renal diseases such as hypertension. We recently described a novel aldosterone signaling network involving Dot1a, AF9, SGK1 and ENaC. Under the basal condition, Dot1a forms a nuclear complex with AF9 and represses ENaC transcription by methylating histone H3 lysine 79 associated with the ENaC promoter. Aldosterone relieves Dot1a-AF9-mediated repression by downregulating expression of Dot1a and AF9, and by impairing Dot1a-AF9 interaction through SGK1-catalyzed AF9 phosphorylation. We are generating a tissue-specific Dot1a-defficient mouse model to validate these findings in vivo. I am also interested in Dot1a function in other biological processes, particularly in tumorigenesis. We have obtained preliminary data suggesting that Dot1a is involved in multiple types of malignancies including kidney and breast cancers. We are using a Tamoxifen-inducible Cre-loxP system to develop a mouse model in which global Dot1a inactivation can be achieved in a temporal fashion. By controlling the time points of Tamoxifen administration, we can generate a series of mouse lines with Dot1a function abolished at different developmental stages. Characterization of these mutant mouse phenotypes will uncover a more complete profile of the Dot1a function in vivo.
Depending on the student’s interests, a tutorial in my laboratory would provide experience with tissue culture and transfection, basic cloning methods, site-directed mutagenesis, real-time qPCR or RT-qPCR, genotyping of various mouse models, Western blot analysis, luciferase assays, and/or measurement of Na+ transport.