The molecular mechanisms of transcriptional regulation are highly conserved among eukaryotes. 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. Much of the work in this laboratory combines genetic, molecular, and genomic approaches available in yeast to address fundamental questions about transcriptional regulatory mechanisms in living cells. In addition, we are defining physiological targets of human transcriptional regulatory proteins and chromatin modifications on a whole-genome basis using a novel microarray approach.
Transcriptional mechanisms in yeast: Current projects include 1) growth-regulated expression of ribosomal protein genes and activator-specific recruitment of TFIID, 2) novel aspects of signal transduction and gene regulation that occur during the response to osmotic stress, 3) how specific components of the basic transcription machinery are recruited to promoters in vivo under genetically and environmentally defined conditions, 4) mechanisms of global repression and gene silencing.
Relationship between chromatin structure and gene expression: Questions of interest include 1) the molecular basis for the relationship between histone acetylation and methylation with transcriptional activity, 2) genome-wide chromatin immunoprecipitation to determine whether and how individual nucleosome remodeling or histone modifying complexes are recruited to specific promoters, 3) a novel mechanism by which promoter regions are more accessible to nuclear proteins than non-promoter regions, 4) dynamics of chromatin modification in vivo .
Functional genomics in mammalian cells: Using high density, whole-genome microarrays, we are mapping binding sites for transcription regulatory proteins, chromatin-modifying activities, and histone modifications in an unbiased manner across the entire human genome. In addition, we are using this methodology to determine the regulatory circuitry by which normal cells undergo the transition to transformed cells in a genetically defined model in which cellular transformation is induced by the Src oncoprotein.
Ng, H.H., Robert, F., Young, R.A., and Struhl, K. (2003). Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol. Cell 11 709-719.
Cawley, S., Bekiranov, S., Ng, H.H., Kapranov, P., Sekinger, E.A., Kampa, D., Piccolboni, A., Sementchenko, V., Cheng, J., Williams, A., Wheeler, R., Wong, B., Drenkow, J., Yamanaka, M., Patel, S., Brubaker, S., Tammana, H., Helt, G., Struhl, K. and Gingeras, T. R. (2004). Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of non-coding RNAs. Cell 116 499-509.
Proft, M. and Struhl, K. (2004). MAP kinase-mediated stress relief that precedes and regulates the timing of transcriptional induction. Cell 118 351-361.
Wade, J.T., Hall, D.B., and Struhl, K. (2004). The transcription factor Ifh1 is a key regulator of yeast ribosomal protein genes. Nature 432 1054-1058.
Mason, P.B. and Struhl, K. (2005). Distinction and relationship between elongation rate and processivity of RNA polymerase II in vivo. Mol. Cell. 17 831-840. Sekinger, E.A., Moqtaderi, Z., and Struhl, K. (2005). Intrinsic histone-DNA interactions and low nucleosome density are important for preferential accessibility of promoter regions in yeast. Mol. Cell. 18 735-748.
Katan-Khaykovich, Y. and Struhl, K. (2005). Heterochromatin formation involves changes in histone modifications over multiple cell generations. EMBO J. 24 2138-2149.
Proft, M., Mas, G., de Nadal, E., Vendrell, A., Noriega, N., Struhl, K., and Posas, F. (2006). The stress-activated Hog1 kinase is a selective transcriptional elongation factor for genes responding to osmotic stress. Mol. Cell. 23 241-250.
Yang, A., Zhu, Z., Kapranov, P., McKeon, F., Church, G.M., Gingeras, T.R., and Struhl, K. (2006). Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. Mol. Cell. 24 593-602.