Fellowship Hui Ren: Zhx2, A New Gene for Hyperlipidemia, Post-Transcriptionally Regulating Gene Expression in a Promoter Dependent Manner

~tharoicImU laths n*r sinai aaftnaty heart noses and sVoS. ~nrc ~ as well as envi-onntntal factors contribute to tf~s disease. A recent collabcwston etween our lab and the lab of [Jr. Jalne Lusis at UCLA has revealed that Zinc ringers and horreoboxea 2 (Zhx2) is the gene responsible for the hyperipidenia/atherosclerosis phenotype defined by t-lyplip2 (Accepted, )rculation: Cardiovascular Geneucs). Furthermore, studies it, our lab and lhe Lusis lab have shown that several hepat enzymes involved in ipid homeostasis are targets of Zhx2 regulation. Thus, a greater understanding of the mechanism by hich Zhx2 regulates target genes nay shed light on lhe genetic influence on atherosclerosis and is therefore of substantal clinical significance. Thx2 was ideritfied in our lab by positional cloning- Zhx2 functions ass repressor slpha-fetoprotein ~AFP) and H19 gene expression in the aduk liver. Our recent data show that Zhx2 does not ater the transcription rate across lhe AFngene but rather, represses AFP nRNLA accuntilaton by inhibiting spicing of several APP `eons, in a pron'oter dependent mnanner `hypothesize that Zhx2 acts through the pronoter of its target genes to affect the splicing of nascent Rt~, thus post- renscriptionally dow n-regulating the level of fully processed rrfif-IA. To test this - iypotheais and to understand this noveL mechanism of gene regulation, I propose lidentify AFP promoter sequence and Zhx2 protein domains required fer