Fajun Yang, Ph.D.
Our lab is interested in elucidating how nutrients regulate metabolism and developmental processes. The sterol regulatory element binding protein (SREBP) family of basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factors are master regulators of both lipid and cholesterol homeostasis. SREBP proteins are synthesized as precursors that are tethered to the endoplasmic reticulum (ER) membrane. In response to decreased cellular levels of sterols, SREBP precursors are proteolytically processed to mature forms that migrate into the nucleus, recruit co-activators, and activate transcription of target genes, such as fatty acid synthase. Currently, our research is focused on understanding how SREBP-mediated transcription is regulated in response to nutrient availability. With the ultimate goal of identifying targets for preventing or treating metabolic syndrome, the aim of our research is to advance our knowledge of how lipid homeostasis is regulated at the molecular levels.
Examples of current projects in our lab:
1. Roles of the Mediator complex in controlling lipid homeostasis: Co-activators, including the histone acetyltransferases CBP/p300 and the Mediator complex, are involved in activating transcription of SREBP target genes. The Mediator is a multi-subunit protein complex. Biochemical and genetic approaches are being taken to study the roles of the Mediator subunits in SREBP-mediated transcription.
2. Functions of the SIRT1 complex in lipogenesis and adipogenesis: Molecular mechanisms of SREBP degradation during fasting are being studied. SREBP protein stability can be regulated by acetylation. Recently, we have observed that the NAD-dependent histone deacetylase SIRT1 orthologs negatively control the expression of SREBP target genes in human cells, C. elegans and Drosophila, consistent with the inverse relationship between SIRT1 and SREBP protein levels during fasting. Thus, SIRT1 may play a key role in mediating down-regulation of SREBP proteins during fasting. More interestingly, we have also found that SIRT1 is physically and functionally associated with multi-functional protein complexes. We are currently studying the functions of the novel SIRT1 complexes in regulating SREBP functions as well as adipogenesis.
1. Morris EJ*, Ji JY*, Yang F, Di Stefano L, Herr A, Moon N, Kwon E, Haigis KM, Näär AM, Dyson NJ. E2F1 represses β-catenin transcription and is antagonized by both pRB and CDK8. 2008 Nature, 455(7212): 552-556. (*Co-first authors)
2. Thakur JK*, Arthanari H*, Yang F*, Pan SJ, Fan X, Breger J, Frueh DP, Gulshan K, Li DK, Mylonalis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Näär AM. A nuclear receptor-like pathway regulating multidrug resistance in fungi. 2008 Nature (Article), 452(7187): 604-609. (*Co-first authors)
3. Yang F*, Vought BW*, Satterlee JS, Walker AK, Sun ZY, Watts JL, DeBeaumont R, Saito RM, Hyberts SG, Yang S, Macol C, Lyer L, Tjian R, van den Heuvel S, Hart AC, Wagner G, Näär AM. An ARC/Mediator subunit required for SREBP control of cholesterol and lipid homeostasis. 2006 Nature, 442(7103): 700-7004. (*Co-first authors)
4. Yang F, DeBeaumont R, Zhou S, Näär AM. The activator-recruited cofactor/Mediator coactivator subunit ARC92 is a functionally important target of the VP16 transcriptional activator. 2004 PNAS, 101(8): 2339-2344.
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