Photo of Kevin Struhl,  PhD

Kevin Struhl, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-2104
Fax: (617) 432-2529


kevin@hms.harvard.edu

Kevin Struhl, PhD

Harvard Medical School

EDUCATIONAL TITLES

  • David Wesley Gaiser Professor, Biological Chemistry and Molecular Pharmacology, Harvard Medical School

DF/HCC PROGRAM AFFILIATION

Research Abstract

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 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.

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) role of microRNAs at various stages of cellular transformation including potential connections to chromatin, 4) mechanistic analysis of the connection between lipid metabolism and transformation, 5) testing metformin as a potential anti-cancer drug.

 

Publications

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  • Ji Z, Song R, Huang H, Regev A, Struhl K. Transcriptome-scale RNase-footprinting of RNA-protein complexes. Nat Biotechnol 2016; 34:410-3. PubMed
  • Rotem A, Janzer A, Izar B, Ji Z, Doench JG, Garraway LA, Struhl K. Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation. Proc Natl Acad Sci U S A 2015; 112:5708-13. PubMed
  • Jin Y, Geisberg JV, Moqtaderi Z, Ji Z, Hoque M, Tian B, Struhl K. Mapping 3' mRNA isoforms on a genomic scale. Curr Protoc Mol Biol 2015; 110:4.23.1-4.23.17. PubMed
  • Fleming JD, Giresi PG, Lindahl-Allen M, Krall EB, Lieb JD, Struhl K. STAT3 acts through pre-existing nucleosome-depleted regions bound by FOS during an epigenetic switch linking inflammation to cancer. Epigenetics Chromatin 2015; 8:7. PubMed
  • Janzer A, German NJ, Gonzalez-Herrera KN, Asara JM, Haigis MC, Struhl K. Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells. Proc Natl Acad Sci U S A 2014; 111:10574-9. PubMed
  • Struhl K. Is DNA methylation of tumour suppressor genes epigenetic? Elife 2014; 3:e02475. PubMed
  • Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci U S A 2013; 110:972-7. PubMed
  • Hughes AL, Jin Y, Rando OJ, Struhl K. A functional evolutionary approach to identify determinants of nucleosome positioning: a unifying model for establishing the genome-wide pattern. Mol Cell 2012; 48:5-15. PubMed
  • Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altshuler RC, Birney E, Brown JB, Cheng C, Djebali S, Dong X, Dunham I, Ernst J, Furey TS, Gerstein M, Giardine B, Greven M, Hardison RC, Harris RS, Herrero J, Hoffman MM, Iyer S, Kellis M, Khatun J, Kheradpour P, Kundaje A, Lassmann T, Li Q, Lin X, Marinov GK, Merkel A, Mortazavi A, Parker SC, Reddy TE, Rozowsky J, Schlesinger F, Thurman RE, Wang J, Ward LD, Whitfield TW, Wilder SP, Wu W, Xi HS, Yip KY, Zhuang J, Pazin MJ, Lowdon RF, Dillon LA, Adams LB, Kelly CJ, Zhang J, Wexler JR, Green ED, Good PJ, Feingold EA, Bernstein BE, Birney E, Crawford GE, Dekker J, Elnitski L, Farnham PJ, Gerstein M, Giddings MC, Gingeras TR, Green ED, Guigó R, Hardison RC, Hubbard TJ, Kellis M, Kent W, Lieb JD, Margulies EH, Myers RM, Snyder M, Stamatoyannopoulos JA, Tenenbaum SA, Weng Z, White KP, Wold B, Khatun J, Yu Y, Wrobel J, Risk BA, Gunawardena HP, Kuiper HC, Maier CW, Xie L, Chen X, Giddings MC, Bernstein BE, Epstein CB, Shoresh N, Ernst J, Kheradpour P, Mikkelsen TS, Gillespie S, Goren A, Ram O, Zhang X, Wang L, Issner R, Coyne MJ, Durham T, Ku M, Truong T, Ward LD, Altshuler RC, Eaton ML, Kellis M, Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Batut P, Bell I, Bell K, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena HP, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Li G, Luo OJ, Park E, Preall JB, Presaud K, Ribeca P, Risk BA, Robyr D, Ruan X, Sammeth M, Sandhu KS, Schaeffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Hayashizaki Y, Harrow J, Gerstein M, Hubbard TJ, Reymond A, Antonarakis SE, Hannon GJ, Giddings MC, Ruan Y, Wold B, Carninci P, Guigó R, Gingeras TR, Rosenbloom KR, Sloan CA, Learned K, Malladi VS, Wong MC, Barber GP, Cline MS, Dreszer TR, Heitner SG, Karolchik D, Kent W, Kirkup VM, Meyer LR, Long JC, Maddren M, Raney BJ, Furey TS, Song L, Grasfeder LL, Giresi PG, Lee BK, Battenhouse A, Sheffield NC, Simon JM, Showers KA, Safi A, London D, Bhinge AA, Shestak C, Schaner MR, Kim SK, Zhang ZZ, Mieczkowski PA, Mieczkowska JO, Liu Z, McDaniell RM, Ni Y, Rashid NU, Kim MJ, Adar S, Zhang Z, Wang T, Winter D, Keefe D, Birney E, Iyer VR, Lieb JD, Crawford GE, Li G, Sandhu KS, Zheng M, Wang P, Luo OJ, Shahab A, Fullwood MJ, Ruan X, Ruan Y, Myers RM, Pauli F, Williams BA, Gertz J, Marinov GK, Reddy TE, Vielmetter J, Partridge E, Trout D, Varley KE, Gasper C, Bansal A, Pepke S, Jain P, Amrhein H, Bowling KM, Anaya M, Cross MK, King B, Muratet MA, Antoshechkin I, Newberry KM, McCue K, Nesmith AS, Fisher-Aylor KI, Pusey B, DeSalvo G, Parker SL, Balasubramanian S, Davis NS, Meadows SK, Eggleston T, Gunter C, Newberry J, Levy SE, Absher DM, Mortazavi A, Wong WH, Wold B, Blow MJ, Visel A, Pennachio LA, Elnitski L, Margulies EH, Parker SC, Petrykowska HM, Abyzov A, Aken B, Barrell D, Barson G, Berry A, Bignell A, Boychenko V, Bussotti G, Chrast J, Davidson C, Derrien T, Despacio-Reyes G, Diekhans M, Ezkurdia I, Frankish A, Gilbert J, Gonzalez JM, Griffiths E, Harte R, Hendrix DA, Howald C, Hunt T, Jungreis I, Kay M, Khurana E, Kokocinski F, Leng J, Lin MF, Loveland J, Lu Z, Manthravadi D, Mariotti M, Mudge J, Mukherjee G, Notredame C, Pei B, Rodriguez JM, Saunders G, Sboner A, Searle S, Sisu C, Snow C, Steward C, Tanzer A, Tapanari E, Tress ML, van Baren MJ, Walters N, Washietl S, Wilming L, Zadissa A, Zhang Z, Brent M, Haussler D, Kellis M, Valencia A, Gerstein M, Reymond A, Guigó R, Harrow J, Hubbard TJ, Landt SG, Frietze S, Abyzov A, Addleman N, Alexander RP, Auerbach RK, Balasubramanian S, Bettinger K, Bhardwaj N, Boyle AP, Cao AR, Cayting P, Charos A, Cheng Y, Cheng C, Eastman C, Euskirchen G, Fleming JD, Grubert F, Habegger L, Hariharan M, Harmanci A, Iyengar S, Jin VX, Karczewski KJ, Kasowski M, Lacroute P, Lam H, Lamarre-Vincent N, Leng J, Lian J, Lindahl-Allen M, Min R, Miotto B, Monahan H, Moqtaderi Z, Mu XJ, O'Geen H, Ouyang Z, Patacsil D, Pei B, Raha D, Ramirez L, Reed B, Rozowsky J, Sboner A, Shi M, Sisu C, Slifer T, Witt H, Wu L, Xu X, Yan KK, Yang X, Yip KY, Zhang Z, Struhl K, Weissman SM, Gerstein M, Farnham PJ, Snyder M, Tenenbaum SA, Penalva LO, Doyle F, Karmakar S, Landt SG, Bhanvadia RR, Choudhury A, Domanus M, Ma L, Moran J, Patacsil D, Slifer T, Victorsen A, Yang X, Snyder M, Auer T, Centanin L, Eichenlaub M, Gruhl F, Heermann S, Hoeckendorf B, Inoue D, Kellner T, Kirchmaier S, Mueller C, Reinhardt R, Schertel L, Schneider S, Sinn R, Wittbrodt B, Wittbrodt J, Weng Z, Whitfield TW, Wang J, Collins PJ, Aldred SF, Trinklein ND, Partridge EC, Myers RM, Dekker J, Jain G, Lajoie BR, Sanyal A, Balasundaram G, Bates DL, Byron R, Canfield TK, Diegel MJ, Dunn D, Ebersol AK, Frum T, Garg K, Gist E, Hansen R, Boatman L, Haugen E, Humbert R, Jain G, Johnson AK, Johnson EM, Kutyavin TV, Lajoie BR, Lee K, Lotakis D, Maurano MT, Neph SJ, Neri FV, Nguyen ED, Qu H, Reynolds AP, Roach V, Rynes E, Sabo P, Sanchez ME, Sandstrom RS, Sanyal A, Shafer AO, Stergachis AB, Thomas S, Thurman RE, Vernot B, Vierstra J, Vong S, Wang H, Weaver MA, Yan Y, Zhang M, Akey JM, Bender M, Dorschner MO, Groudine M, MacCoss MJ, Navas P, Stamatoyannopoulos G, Kaul R, Dekker J, Stamatoyannopoulos JA, Dunham I, Beal K, Brazma A, Flicek P, Herrero J, Johnson N, Keefe D, Lukk M, Luscombe NM, Sobral D, Vaquerizas JM, Wilder SP, Batzoglou S, Sidow A, Hussami N, Kyriazopoulou-Panagiotopoulou S, Libbrecht MW, Schaub MA, Kundaje A, Hardison RC, Miller W, Giardine B, Harris RS, Wu W, Bickel PJ, Banfai B, Boley NP, Brown JB, Huang H, Li Q, Li JJ, Noble WS, Bilmes JA, Buske OJ, Hoffman MM, Sahu AD, Kharchenko PV, Park PJ, Baker D, Taylor J, Weng Z, Iyer S, Dong X, Greven M, Lin X, Wang J, Xi HS, Zhuang J, Gerstein M, Alexander RP, Balasubramanian S, Cheng C, Harmanci A, Lochovsky L, Min R, Mu XJ, Rozowsky J, Yan KK, Yip KY, Birney E. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489:57-74. PubMed
  • Polytarchou C, Iliopoulos D, Struhl K. An integrated transcriptional regulatory circuit that reinforces the breast cancer stem cell state. Proc Natl Acad Sci U S A 2012; 109:14470-5. PubMed
  • Barber MF, Michishita-Kioi E, Xi Y, Tasselli L, Kioi M, Moqtaderi Z, Tennen RI, Paredes S, Young NL, Chen K, Struhl K, Garcia BA, Gozani O, Li W, Chua KF. SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation. Nature 2012; 487:114-8. PubMed
  • Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 2011. PubMed
  • Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A 2011; 108:1397-402. PubMed
  • Katan-Khaykovich Y, Struhl K. Splitting of H3-H4 tetramers at transcriptionally active genes undergoing dynamic histone exchange. Proc Natl Acad Sci U S A 2011; 108:1296-301. PubMed
  • Locke G, Tolkunov D, Moqtaderi Z, Struhl K, Morozov AV. High-throughput sequencing reveals a simple model of nucleosome energetics. Proc Natl Acad Sci U S A 2010; 107:20998-1003. PubMed
  • Fan X, Moqtaderi Z, Jin Y, Zhang Y, Liu XS, Struhl K. Nucleosome depletion at yeast terminators is not intrinsic and can occur by a transcriptional mechanism linked to 3'-end formation. Proc Natl Acad Sci U S A 2010; 107:17945-50. PubMed
  • Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell 2010; 39:761-72. PubMed
  • Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell 2010; 39:493-506. PubMed
  • Moqtaderi Z, Wang J, Raha D, White RJ, Snyder M, Weng Z, Struhl K. Genomic binding profiles of functionally distinct RNA polymerase III transcription complexes in human cells. Nat Struct Mol Biol 2010; 17:635-40. PubMed
  • Hirsch HA, Iliopoulos D, Joshi A, Zhang Y, Jaeger SA, Bulyk M, Tsichlis PN, Shirley Liu X, Struhl K. A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases. Cancer Cell 2010; 17:348-61. PubMed
  • Raha D, Wang Z, Moqtaderi Z, Wu L, Zhong G, Gerstein M, Struhl K, Snyder M. Close association of RNA polymerase II and many transcription factors with Pol III genes. Proc Natl Acad Sci U S A 2010; 107:3639-44. PubMed
  • Miotto B, Struhl K. HBO1 histone acetylase activity is essential for DNA replication licensing and inhibited by Geminin. Mol Cell 2010; 37:57-66. PubMed
  • Yang A, Zhu Z, Kettenbach A, Kapranov P, McKeon F, Gingeras TR, Struhl K. Genome-wide mapping indicates that p73 and p63 co-occupy target sites and have similar dna-binding profiles in vivo. PLoS ONE 2010; 5:e11572. PubMed
  • Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 2009; 139:693-706. PubMed
  • Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69:7507-11. PubMed
  • Auerbach RK, Euskirchen G, Rozowsky J, Lamarre-Vincent N, Moqtaderi Z, Lefrançois P, Struhl K, Gerstein M, Snyder M. Mapping accessible chromatin regions using Sono-Seq. Proc Natl Acad Sci U S A 2009; 106:14926-31. PubMed
  • Zhang Y, Moqtaderi Z, Rattner BP, Euskirchen G, Snyder M, Kadonaga JT, Liu XS, Struhl K. Intrinsic histone-DNA interactions are not the major determinant of nucleosome positions in vivo. Nat Struct Mol Biol 2009; 16:847-52. PubMed
  • Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, Tsichlis PN. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci Signal 2009; 2:ra62. PubMed
  • Fan X,Struhl K. Where does mediator bind in vivo? PLoS ONE 2009; 4:e5029. PubMed
  • Fan X,Lamarre-Vincent N,Wang Q,Struhl K. Extensive chromatin fragmentation improves enrichment of protein binding sites in chromatin immunoprecipitation experiments. Nucleic Acids Res 2008; 36:e125. PubMed
  • Madhani HD,Francis NJ,Kingston RE,Kornberg RD,Moazed D,Narlikar GJ,Panning B,Struhl K. Epigenomics: a roadmap, but to where? Science 2008; 322:43-4. PubMed
  • Struhl K. The hisB463 mutation and expression of a eukaryotic protein in Escherichia coli. Genetics 2008; 180:709-14. PubMed
  • Miotto B,Struhl K. HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1. Genes Dev 2008; 22:2633-8. PubMed
  • Thakur JK, Arthanari H, Yang F, Pan SJ, Fan X, Breger J, Frueh DP, Gulshan K, Li DK, Mylonakis E, Struhl K, Moye-Rowley WS, Cormack BP, Wagner G, Naar AM. A nuclear receptor-like pathway regulating multidrug resistance in fungi. Nature 2008; 452:604-9. PubMed
  • Moqtaderi Z, Struhl K. Expanding the repertoire of plasmids for PCR-mediated epitope tagging in yeast. Yeast 2008; 25:287-92. PubMed
  • Johnson DS, Li W, Gordon DB, Bhattacharjee A, Curry B, Ghosh J, Brizuela L, Carroll JS, Brown M, Flicek P, Koch CM, Dunham I, Bieda M, Xu X, Farnham PJ, Kapranov P, Nix DA, Gingeras TR, Zhang X, Holster H, Jiang N, Green RD, Song JS, McCuine SA, Anton E, Nguyen L, Trinklein ND, Ye Z, Ching K, Hawkins D, Ren B, Scacheri PC, Rozowsky J, Karpikov A, Euskirchen G, Weissman S, Gerstein M, Snyder M, Yang A, Moqtaderi Z, Hirsch H, Shulha HP, Fu Y, Weng Z, Struhl K, Myers RM, Lieb JD, Liu XS. Systematic evaluation of variability in ChIP-chip experiments using predefined DNA targets. Genome Res 2008; 18:393-403. PubMed
  • Schwabish MA, Struhl K. The Swi/Snf complex is important for histone eviction during transcriptional activation and RNA polymerase II elongation in vivo. Mol Cell Biol 2007; 27:6987-95. PubMed
  • Miotto B, Struhl K. [Histone H4 lysine 16 acetylation: from genome regulation to tumoral progression] Med Sci (Paris) 2007; 23:735-40. PubMed
  • Peckham HE, Thurman RE, Fu Y, Stamatoyannopoulos JA, Noble WS, Struhl K, Weng Z. Nucleosome positioning signals in genomic DNA. Genome Res 2007; 17:1170-7. PubMed
  • Wade JT, Struhl K, Busby SJ, Grainger DC. Genomic analysis of protein-DNA interactions in bacteria: insights into transcription and chromosome organization. Mol Microbiol 2007; 65:21-6. PubMed
  • , Birney E, Stamatoyannopoulos JA, Dutta A, Guig. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007; 447:799-816. PubMed
  • Ghosh S, Hirsch HA, Sekinger EA, Kapranov P, Struhl K, Gingeras TR. Differential analysis for high density tiling microarray data. BMC Bioinformatics 2007; 8:359. PubMed
  • Reppas NB, Wade JT, Church GM, Struhl K. The transition between transcriptional initiation and elongation in E. coli is highly variable and often rate limiting. Mol Cell 2006; 24:747-57. PubMed
  • Yang A, Zhu Z, Kapranov P, McKeon F, Church GM, Gingeras TR, Struhl K. Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. Mol Cell 2006; 24:593-602. PubMed
  • Wade JT, Roa DC, Grainger DC, Hurd D, Busby SJ, Struhl K, Nudler E. Extensive functional overlap between sigma factors in Escherichia coli. Nat Struct Mol Biol 2006; 13:806-14. PubMed
  • Proft M, Mas G, de Nadal E, Vendrell A, Noriega N, Struhl K, Posas F. The stress-activated Hog1 kinase is a selective transcriptional elongation factor for genes responding to osmotic stress. Mol Cell 2006; 23:241-50. PubMed
  • Schwabish MA, Struhl K. Asf1 mediates histone eviction and deposition during elongation by RNA polymerase II. Mol Cell 2006; 22:415-22. PubMed
  • Hall DB, Wade JT, Struhl K. An HMG protein, Hmo1, associates with promoters of many ribosomal protein genes and throughout the rRNA gene locus in Saccharomyces cerevisiae. Mol Cell Biol 2006; 26:3672-9. PubMed
  • Fan X, Chou DM, Struhl K. Activator-specific recruitment of Mediator in vivo. Nat Struct Mol Biol 2006; 13:117-20. PubMed
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