Biological Chemistry and Molecular Pharmacology
Transcriptional regulation in response to environmental and developmental cues is mediated by the combinatorial and synergistic action of specific DNA-binding activators and repressors on components of the general transcription machinery and chromatin modifying activities, and it also involves microRNAs. We combine genetic, molecular, genomic, and evolutionary approaches to address fundamental questions about transcriptional regulatory mechanisms, mRNA stability, and 3’ end formation in yeast, as well as elucidating the transcriptional regulatory circuits that mediate the process of cellular transformation and formation of cancer stem cells.
Relationship between transcriptional regulatory mechanisms and chromatin structure in yeast: Current projects include 1) how co-activators, chromatin-modifying complexes, repressors, and components of the basic transcription machinery are recruited to promoters in vivo under genetically and environmentally defined conditions, 2) intrinsic and dynamic aspects of chromatin structure, and mechanisms of epigenetic inheritance of heterochromatic and euchromatic states, 3) distinguishing between biological function and biological noise using evolutionarily related yeast species and other approaches.
mRNA stability and 3’ end formation in yeast: Current projects include 1) selection of polyadenylation sites, 2) mechanism of mRNA decay including the identification of stabilizing and destabilizing sequences and the role of secondary structure, 3) regulation of 3’ end formation and mRNA stability under different environmental conditions by RNA-binding proteins
Transcriptional regulatory circuits during the process of cellular transformation in human cells: Current projects include 1) an epigenetic switch from non-transformed to transformed cells in response to a transient inflammatory signal, 2) molecular pathways required for the formation of cancer stem cells, 3) defining an inflammatory index to type human cancers, 4) phenotypic screening methods for personalized therapy for human cancer patients, 5) testing metformin as a potential anti-cancer drug.
We combine genetic, molecular, biochemical, genomic, and evolutionary approaches to study the mechanistic relationship between chromatin structure and transcriptional regulation and its implications for epigenetic inheritance of heterochromatin. In addition, we combine functional genomic and mechanistic approaches to elucidate the transcriptional regulatory circuits involved in the process of cellular transformation and formation of cancer stem cells, and the use of metformin as an anti-cancer drug in combination with chemotherapy.
(https://struhl.med.harvard.edu/node/33 for complete list and PDF files)
Hirsch, H.A., Iliopoulos, D., Tsichlis, P.N., and Struhl, K. (2009). Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69 7507-7511.
Iliopoulos, D., Hirsch, H.A., and Struhl, K. (2009). An epigenetic switch involving NF-kB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell 139 693-706.
Hirsch, H.A., Iliopoulos, D., Joshi, A., Zhong, Y., Jaeger, S.A., Bulyk, M.L, Tsichlis, P.N. Liu, X.S., and Struhl, K. (2010). A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases. Cancer Cell 17 348-361.
Wong, K.H. and Struhl, K. (2011). The Cyc8-Tup1 complex inhibits transcription primarily by masking the activation domain of the recruiting protein. Genes Dev. 25 2525-2539.
Polytarchou, C., Iliopoulos, D., and Struhl, K. (2012). An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state. Proc. Natl. Acad. Sci. U.S.A. 109 14470-14475.
Hughes, A., Jin, Y., Rando, O.J., and Struhl, K. (2012). A functional evolutionary approach to identify determinants of nucleosome positioning: A unifying model for establishing the genome-wide pattern. Mol. Cell 48 5-15.
Hirsch, H.A., Iliopoulos, D., and Struhl, K. (2013). Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc. Natl. Acad. Sci. US.A. 110 972-977.
Geisberg, J.V., Moqtaderi, Z., Fan, X., Ozsolak, F., and Struhl, K. (2014). Global analysis of mRNA isoform half-lives reveals stabilizing and destabilizing elements in yeast. Cell 156 812-824.
Wong, K.H., Jin, Y., and Struhl, K. (2014). TFIIH phosphorylation of the Pol II CTD stimulates Mediator dissociation from the preinitiation complex and promoter escape. Mol. Cell. 54 601-612.
Ji, Z., Song, R., Regev, A., and Struhl, K. (2015). Many lncRNAs, 5’UTRs, and pseudogenes are translated and some are likely to express functional proteins. eLife 4 e08890.
Miotto, B. Ji, Z., and Struhl, K. (2016). Selectivity of ORC binding sites and the relation to replication timing, fragile sites, and deletions in cancers. Proc. Natl. Acad. Sci. U.S.A. 113 E4810-E4819.