Kevin White, Ph.D.

On leave 3.01.17 through 3.31.18

Research Description

The White lab studies the coordinated action of networks of genes that control developmental, disease and evolutionary processes. We have particular focus on discovery of genetic factors that contribute to cancer development and progression, and on building genome-wide models of transcriptional networks. We use an integrated approach that makes use of genome and transcriptome sequencing, large-scale protein-protein and protein-DNA interaction analyses, measurement of chromatin state, systematic RNAi and CRISPR mutational analysis, and high throughput functional analyses of genomic regulatory elements. By applying our methods to both closely and distantly related species, we are investigating how conserved molecular networks control basic developmental processes and how variation in molecular networks translates into variation in organismal phenotypes.

We are also particularly interested in the transcriptional networks controlled by nuclear receptor proteins in development and disease. For example, we have produced genome-wide maps of the entire repertoire of nuclear receptors expressed in breast cancer cells, and this has led to the discovery of previously untargeted nuclear receptors that are promising drug candidates. We then test such candidates in mouse models, and we are attempting to ‘reverse engineer’ the nuclear receptor regulatory networks in breast cancer using a combination of genome-scale data generation, computational techniques and genomic engineering of cell lines and mice. We also have recently built novel algorithms for discovering tumor drivers and tumor risk factors from large-scale sequencing data, such as those available from The Cancer Genome Atlas. In those projects we have identified significantly co-occurring mutations and tested for genetic interactions in cell lines and in patient survival data, we have identified dozens of novel fusion genes and then synthesized them for testing in cell and mouse models, and we have systematically identified germline variants that may contribute to cancer risk and tested their functional roles using CRISPR engineered cell models.

Another focus of the lab is studying genetic regulatory programs that are highly conserved between fly and human. This has led to discoveries such as a role for the protein SPOP in bothDrosophila embryogenesis and human kidney cancer, and to the identification of conserved targets of natural selection during adaptation to hypoxia (low oxygen) in both flies and humans. Related to this comparative work is our lab’s contributions to the ENCODE and modENCODE projects, where we have been systematically comparing the binding patterns of transcription factors genome-wide in flies, worms and humans. Our lab also contributes to the NIH GTEx and psychENCODE projects through our investigations of the relationship between genomic variation and variation in transcript and protein expression.

Finally, we have recently embarked on an ambitious project in pancreatic cancer to co-analyze large numbers of tumor genomes, tens of thousands of electronic medical records, and literature databases to build predictive models of which patients might respond to which treatments. This work is facilitated by the use of patient-derived xenograft models, as well as mouse models developed using the CRISPR Cas9 system. Our goal is to develop algorithmic approaches to rapidly assess a tumor’s genomic and physiological state, then test drugs in mouse models that ultimately can be moved into patients.

Selected Publications

Comparative analysis of regulatory information and circuits across distant species. Boyle AP, Araya CL, Brdlik C, Cayting P, Cheng C, Cheng Y, Gardner K, Hillier LW, Janette J, Jiang L, Kasper D, Kawli T, Kheradpour P, Kundaje A, Li JJ, Ma L, Niu W, Rehm EJ, Rozowsky J, Slattery M, Spokony R, Terrell R, Vafeados D, Wang D, Weisdepp P, Wu YC, Xie D, Yan KK, Feingold EA, Good PJ, Pazin MJ, Huang H, Bickel PJ, Brenner SE, Reinke V, Waterston RH, Gerstein M, White KP, Kellis M, Snyder M. (2014 Aug) Nature. 2014 Aug 28;512(7515):453-6. doi: 10.1038/nature13668. 25164757

The spectrum of somatic mutations in high-risk acute myeloid leukaemia with -7/del(7q). McNerney ME, Brown CD, Peterson AL, Banerjee M, Larson RA, Anastasi J, Le Beau MM, White KP. (2014 Aug) Br J Haematol. 2014 Aug;166(4):550-6. doi: 10.1111/bjh.12964. Epub 2014 Jun 13.24931631

Evolution of H3K27me3-marked chromatin is linked to gene expression evolution and to patterns of gene duplication and diversification. Arthur RK, Ma L, Slattery M, Spokony RF, Ostapenko A, Negre N, White KP. (2014 Jul) Genome Res. 2014 Jul;24(7):1115-24. doi: 10.1101/gr.162008.113. 24985914 (Full Text)

Diverse patterns of genomic targeting by transcriptional regulators in Drosophila melanogaster. Slattery M, Ma L, Spokony RF, Arthur RK, Kheradpour P, Kundaje A, Negre N, Crofts A, Ptashkin R, Zieba J, Ostapenko A, Suchy S, Victorsen A, Jameel N, Grundstad AJ, Gao W, Moran JR, Rehm EJ, Grossman RL, Kellis M, White KP. (2014 Jul) Genome Res. 2014 Jul;24(7):1224-35. doi: 10.1101/gr.168807.113. 24985916 (Full Text)

SPOP promotes tumorigenesis by acting as a key regulatory hub in kidney cancer. Li G, Ci W, Karmakar S, Chen K, Dhar R, Fan Z, Guo Z, Zhang J, Ke Y, Wang L, Zhuang M, Hu S, Li X, Zhou L, Li X, Calabrese MF, Watson ER, Prasad SM, Rinker-Schaeffer C, Eggener SE, Stricker T, Tian Y, Schulman BA, Liu J, White KP. (2014 Apr) Cancer Cell. 2014 Apr 14;25(4):455-68. doi: 10.1016/j.ccr.2014.02.007. Epub 2014 Mar 20.24656772

RNA-seq differential expression studies: more sequence or more replication?Liu Y, Zhou J, White KP. (2014 Feb) Bioinformatics. 2014 Feb 1;30(3):301-4. doi: 10.1093/bioinformatics/btt688. Epub 2013 Dec 6. 24319002 (Full Text)

A comprehensive nuclear receptor network for breast cancer cells. Kittler R, Zhou J, Hua S, Ma L, Liu Y, Pendleton E, Cheng C, Gerstein M, White KP. (2013 Feb) Cell Rep. 2013 Feb 21;3(2):538-51. doi: 10.1016/j.celrep.2013.01.004. Epub 2013 Jan 31.23375374

CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. McNerney ME, Brown CD, Wang X, Bartom ET, Karmakar S, Bandlamudi C, Yu S, Ko J, Sandall BP, Stricker T, Anastasi J, Grossman RL, Cunningham JM, Le Beau MM, White KP. (2013 Feb) Blood. 2013 Feb 7;121(6):975-83. doi: 10.1182/blood-2012-04-426965. Epub 2012 Dec 3.23212519 (Full Text)

Adaptive evolution and the birth of CTCF binding sites in the Drosophila genome. Ni X, Zhang YE, Negre N, Chen S, Long M, White KP. (2012) PLoS Biol. 2012;10(11):e1001420. doi: 10.1371/journal.pbio.1001420. Epub 2012 Nov 6.23139640 (Full Text)

A cis-regulatory map of the Drosophila genome. Negre N, Brown CD, Ma L, Bristow CA, Miller SW, Wagner U, Kheradpour P, Eaton ML, Loriaux P, Sealfon R, Li Z, Ishii H, Spokony RF, Chen J, Hwang L, Cheng C, Auburn RP, Davis MB, Domanus M, Shah PK, Morrison CA, Zieba J, Suchy S, Senderowicz L, Victorsen A, Bild NA, Grundstad AJ, Hanley D, MacAlpine DM, Mannervik M, Venken K, Bellen H, White R, Gerstein M, Russell S, Grossman RL, Ren B, Posakony JW, Kellis M, White KP. (2011 Mar) Nature. 2011 Mar 24;471(7339):527-31. doi: 10.1038/nature09990. 21430782 (Full Text)

Identification of functional elements and regulatory circuits by Drosophila modENCODE. Roy S, Ernst J, Kharchenko PV, Kheradpour P, Negre N, Eaton ML, Landolin JM, Bristow CA, Ma L, Lin MF, Washietl S, Arshinoff BI, Ay F, Meyer PE, Robine N, Washington NL, Di Stefano L, Berezikov E, Brown CD, Candeias R, Carlson JW, Carr A, Jungreis I, Marbach D, Sealfon R, Tolstorukov MY, Will S, Alekseyenko AA, Artieri C, Booth BW, Brooks AN, Dai Q, Davis CA, Duff MO, Feng X, Gorchakov AA, Gu T, Henikoff JG, Kapranov P, Li R, MacAlpine HK, Malone J, Minoda A, Nordman J, Okamura K, Perry M, Powell SK, Riddle NC, Sakai A, Samsonova A, Sandler JE, Schwartz YB, Sher N, Spokony R, Sturgill D, van Baren M, Wan KH, Yang L, Yu C, Feingold E, Good P, Guyer M, Lowdon R, Ahmad K, Andrews J, Berger B, Brenner SE, Brent MR, Cherbas L, Elgin SC, Gingeras TR, Grossman R, Hoskins RA, Kaufman TC, Kent W, Kuroda MI, Orr-Weaver T, Perrimon N, Pirrotta V, Posakony JW, Ren B, Russell S, Cherbas P, Graveley BR, Lewis S, Micklem G, Oliver B, Park PJ, Celniker SE, Henikoff S, Karpen GH, Lai EC, MacAlpine DM, Stein LD, White KP, Kellis M. (2010 Dec) Science. 2010 Dec 24;330(6012):1787-97. doi: 10.1126/science.1198374. Epub 2010 Dec 22. 21177974 (Full Text)

Genomic antagonism between retinoic acid and estrogen signaling in breast cancer. Hua S, Kittler R, White KP. (2009 Jun) Cell. 2009 Jun 26;137(7):1259-71. doi: 10.1016/j.cell.2009.04.043. 19563758 (Full Text)

Unlocking the secrets of the genome. Celniker SE, Dillon LA, Gerstein MB, Gunsalus KC, Henikoff S, Karpen GH, Kellis M, Lai EC, Lieb JD, MacAlpine DM, Micklem G, Piano F, Snyder M, Stein L, White KP, Waterston RH. (2009 Jun) Nature. 2009 Jun 18;459(7249):927-30. doi: 10.1038/459927a. 19536255 (Full Text)

Analysis of Drosophila segmentation network identifies a JNK pathway factor overexpressed in kidney cancer. Liu J, Ghanim M, Xue L, Brown CD, Iossifov I, Angeletti C, Hua S, Negre N, Ludwig M, Stricker T, Al-Ahmadie HA, Tretiakova M, Camp RL, Perera-Alberto M, Rimm DL, Xu T, Rzhetsky A, White KP. (2009 Feb) Science. 2009 Feb 27;323(5918):1218-22. doi: 10.1126/science.1157669. Epub 2009 Jan 22. 19164706 (Full Text)

Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression. Hua S, Kallen CB, Dhar R, Baquero MT, Mason CE, Russell BA, Shah PK, Liu J, Khramtsov A, Tretiakova MS, Krausz TN, Olopade OI, Rimm DL, White KP. (2008) Mol Syst Biol. 2008;4:188. doi: 10.1038/msb.2008.25. Epub 2008 Apr 15. 18414489 (Full Text)

Expression profiling in primates reveals a rapid evolution of human transcription factors. Gilad Y, Oshlack A, Smyth GK, Speed TP, White KP. (2006 Mar) Nature. 2006 Mar 9;440(7081):242-5. 16525476

A mutation accumulation assay reveals a broad capacity for rapid evolution of gene expression. Rifkin SA, Houle D, Kim J, White KP. (2005 Nov) Nature. 2005 Nov 10;438(7065):220-3. 16281035

A gene expression map for the euchromatic genome of Drosophila melanogaster. Stolc V, Gauhar Z, Mason C, Halasz G, van Batenburg MF, Rifkin SA, Hua S, Herreman T, Tongprasit W, Barbano PE, Bussemaker HJ, White KP. (2004 Oct) Science. 2004 Oct 22;306(5696):655-60. 15499012