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Long, Henry

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Long

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Long, Henry
Author's Publications: search.filters.isAuthorOfPublication.45d55535-c5d2-4aa6-a782-6a5381c02cc8

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    Regulation of the glucocorticoid receptor via a BET-dependent enhancer drives antiandrogen resistance in prostate cancer
    (eLife Sciences Publications, Ltd, 2017) Shah, Neel; Wang, Ping; Wongvipat, John; Karthaus, Wouter R; Abida, Wassim; Armenia, Joshua; Rockowitz, Shira; Drier, Yotam; Bernstein, Bradley; Long, Henry; Freedman, Matthew; Arora, Vivek K; Zheng, Deyou; Sawyers, Charles L
    In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.
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    The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis
    (2015) Pomerantz, Mark; Li, Fugen; Takeda, David; Lenci, Romina; Chonkar, Apurva; Chabot, Matthew; Cejas, Paloma; Vazquez, Francisca; Cook, Jennifer; Shivdasani, Ramesh; Bowden, Michaela; Lis, Rosina; Hahn, William; Kantoff, Philip; Brown, Myles; Loda, Massimo; Long, Henry; Freedman, Matthew
    Master transcription factors interact with DNA to establish cell-type identity and to regulate gene expression in mammalian cells1,2. The genome-wide map of these transcription factor binding sites has been termed the cistrome3. Here we show that the androgen receptor (AR) cistrome undergoes extensive reprogramming during prostate epithelial transformation in man. Using human prostate tissue, we observed a core set of AR binding sites that are consistently reprogrammed in tumors. FOXA1 and HOXB13, co-localized with the reprogrammed AR sites in human tumor tissue. Introduction of FOXA1 and HOXB13 into an immortalized prostate cell line reprogrammed the AR cistrome to resemble that of a prostate tumor, functionally linking these specific factors to AR reprogramming. These findings offer mechanistic insights into a key set of events that drive normal prostate epithelium towards transformation and establish the centrality of epigenetic reprogramming in human prostate tumorigenesis.
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    Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
    (Nature Publishing Group, 2016) Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry; Ingles, Sue A.; Kittles, Rick A.; Strom, Sara S.; Rybicki, Benjamin A.; Nemesure, Barbara; Isaacs, William B.; Zheng, Wei; Pettaway, Curtis A.; Yeboah, Edward D.; Tettey, Yao; Biritwum, Richard B.; Adjei, Andrew A.; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P.; John, Esther M.; Murphy, Adam B.; Signorello, Lisa B; Carpten, John; Leske, M. Cristina; Wu, Suh-Yuh; Hennis, Anslem J. M.; Neslund-Dudas, Christine; Hsing, Ann W.; Chu, Lisa; Goodman, Phyllis J.; Klein, Eric A.; Witte, John S.; Casey, Graham; Kaggwa, Sam; Cook, Michael B.; Stram, Daniel O.; Blot, William J.; Eeles, Rosalind A.; Easton, Douglas; Kote-Jarai, ZSofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G.; Southey, Melissa C.; Fitzgerald, Liesel M.; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E.; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L. J.; Nordestgaard, Børge G.; Key, Tim J.; Travis, Ruth C.; Neal, David E.; Donovan, Jenny L.; Hamdy, Freddie C.; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L.; Thibodeau, Stephen N.; McDonnell, Shannon K.; Schaid, Daniel J.; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S.; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K.; Arndt, Volker; Park, Jong Y.; Sellers, Thomas A.; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A.; Teixeira, Manuel R.; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Cook, Margaret; Guy, Michelle; Govindasami, Koveela; Leongamornlert, Daniel; Sawyer, Emma J.; Wilkinson, Rosemary; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Dadaev, Tokhir; Morgan, Angela; Fisher, Cyril; Hazel, Steve; Livni, Naomi; Lophatananon, Artitaya; Pedersen, John; Hopper, John L.; Adolfson, Jan; Stattin, Paer; Johansson, Jan-Erik; Cavalli-Bjoerkman, Carin; Karlsson, Ami; Broms, Michael; Auvinen, Anssi; Kujala, Paula; Maeaettaenen, Liisa; Murtola, Teemu; Taari, Kimmo; Weischer, Maren; Nielsen, Sune F.; Klarskov, Peter; Roder, Andreas; Iversen, Peter; Wallinder, Hans; Gustafsson, Sven; Cox, Angela; Brown, Paul; George, Anne; Marsden, Gemma; Lane, Athene; Davis, Michael; Tillmans, Lori; Riska, Shaun; Wang, Liang; Rinckleb, Antje; Lubiski, Jan; Stegmaier, Christa; Pow-Sang, Julio; Park, Hyun; Radlein, Selina; Rincon, Maria; Haley, James; Zachariah, Babu; Kachakova, Darina; Popov, Elenko; Mitkova, Atanaska; Vlahova, Aleksandrina; Dikov, Tihomir; Christova, Svetlana; Heathcote, Peter; Wood, Glenn; Malone, Greg; Saunders, Pamela; Eckert, Allison; Yeadon, Trina; Kerr, Kris; Collins, Angus; Turner, Megan; Srinivasan, Srilakshmi; Kedda, Mary-Anne; Alexander, Kimberly; Omara, Tracy; Wu, Huihai; Henrique, Rui; Pinto, Pedro; Santos, Joana; Barros-Silva, Joao; Conti, David V.; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I.; Campa, Daniele; Crawford, E. David; Diver, W. Ryan; Gapstur, Susan M.; Gaziano, John; Giovannucci, Edward; Hoover, Robert; Hunter, David; Johansson, Mattias; Kraft, Phillip; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L.; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R.; Price, Alkes; Freedman, Matthew; Haiman, Christopher A.; Pasaniuc, Bogdan
    Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
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    A closer look into DNase I hypersensitivity
    (BioMed Central, 2013) He, Housheng H; Meyer, Clifford; Long, Henry; Liu, Xiaole; Brown, Myles
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    Enhancer Signatures Stratify and Predict Outcomes of Non-Functional Pancreatic Neuroendocrine Tumors
    (Springer Science and Business Media LLC, 2019-07-01) Cejas, Paloma; Drier, Yotam; Brosens, Lodewijk A. A.; Deshpande, Vikram; Morsink, Folkert H. M.; Graham, Mindy K.; Valk, Gerlof D.; Vriens, Menno R.; Fernandez-Del Castillo, Carlos; Fabiana Lucia da Silva, Annacarolina; Font-Tello, Alba; Heaphy, Christopher M.; Sicinska, Ewa; Dreijerink, Koen; Epstein, Charles; Conemans, Elfi; Ferrone, Cristina; Adar, Tomer; Bowden, Michaela; Whitton, Holly; Long, Henry; Gaskell, Elizabeth; Shoresh, Noam; Kulke, Matthew; Chung, Daniel; Bernstein, Bradley; Shivdasani, Ramesh
    Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered ‘non-functional’. As clinical behaviors vary widely and distant metastases are eventually lethal, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major sub-types whose epigenomes and transcriptomes partially resemble islet alpha and beta cells. Transcription factors ARX and PDX1 specify these normal cells, respectively, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1- tumors and, within this sub-type, in cases with alternative lengthening of telomeres (ALT). These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course, and can inform post-operative clinical decisions.