Kevin Struhl

Department of Biological Chemistry and Molecular Pharmacology
Harvard Medical School
Building C1, Room 315
240 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-2104
Fax: (617) 432-2529
Email: kevin@hms.harvard.edu

Web Page: The Struhl Lab Page
10 postdoctoral students, 1 graduate student

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, genomic, and evolutionary approaches available in yeast to address fundamental questions about transcriptional regulatory mechanisms in living cells. In addition, we are using genome-wide approaches to identify physiological target sites of transcriptional regulatory proteins and the resulting transcriptional regulatory circuits during the process of cellular transformation in human cells.

Relationship between transcriptional regulatory mechanisms and chromatin structure 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 co-activators, chromatin-modifying complexes, and 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, 5) intrinsic and dynamic aspects of chromatin structure in vivo, 6) mechanisms of epigenetic inheritance of heterochromatic and euchromatic states,  7) distinguishing between biological function and biological noise using evolutionarily related yeast species and other approaches.

Transcriptional regulatory circuits during the process of cellular transformation in human cells:  We developed an experimental system in which a normal breast epithelial cell line can be induced to undergo cellular transformation over the course of 24-36 hours.  In addition, we are comparing isogenic fibroblastic cells lines that represent different stages of the transformation process.  Transcriptional profiling reveals a common gene expression signature for cellular transformation that displays striking relationships to inflammation and metabolic syndrome.  Furthermore, we have identified microRNAs and their target genes that are regulated during the transition between normal and transformed cells.  To elucidate the underlying regulatory circuits, physiological targets of human transcriptional regulatory proteins will be determined on a genome-wide scale, and their functional significance established by genetic analysis.

References:

• 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. et al. (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.
• Katan-Khaykovich, Y. and Struhl, K. (2005). Heterochromatin formation involves changes in histone modifications over multiple cell generations. EMBO J. 24 2138-2149.
• 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.
• 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.
• 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.