Shelley L. Berger, Ph.D.

Identification of transcriptional adaptors/coactivators Gcn5/Ada2/Ada3 and discovery of novel histone modifications and mechanisms in transcription. We discovered the first transcriptional adaptors, which we showed associate with DNA binding activators. This was groundbreaking as a new model for transcriptional activation, and set the stage for understanding how histone enzymatic modifiers are recruited to genes. Our work was the first to reveal the importance of adaptor Gcn5 acetylation activity in transcriptional activation, and helped to unify understanding of transcription and chromatin regulation. We discovered numerous novel histone modifications, histone modification cross-talk, and sequential histone modifications in transcription, including histone phosphorylation/acetylation, ubiquitylation/deubiquitylation.

• Berger SL, Piña B, Silverman N, Marcus G, Agapite J, Regier J, Triezenberg S, and Guarente L. (1992) Genetic identification of ADA2, a potential transcriptional adaptor, required for activation by a subset of acidic activation domains. Cell 70:251-265.
• Wang L, Liu L. and Berger SL. (1998) Critical residues for histone acetylation by GCN5, functioning in Ada and SAGA complexes, are also required for transcriptional function in vivo. Genes & Development 12: 640-653.
• Lo W-S, Duggan L, Belotserkovskya R, Emre T, Lane W, Shiekhattar R, and Berger SL. (2001) Snf1 is a histone kinase which works in concert with the histone acetyltransferase Gcn5 to regulate transcription. Science 293:1142-6.
• Henry KW, Wyce A, Lo WS, Emre NCT, Duggan L, Shilatifard A, Osley M, and Berger SL. (2003) Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes & Development, 17,2648-63.

Discovery of tumor suppressor p53 post-translational modifications and their mechanisms including activating p53 acetylation, repressive p53 methylation, and novel chromatin pathways in p53-mediated transcriptional activation. Our work revealed new enzyme modifiers of p53, including acetylation and methylation, and their functions in regulating p53 activity. In particular, we discovered that p53 methylation is generally repressive to its function. These findings spurred broad efforts in discovery of transcription factor modifications. Recently, we discovered novel pathways used by wild type and mutant p53 in regulating chromatin structure/function.

• Huang J, Perez-Burgos L, Placek BJ, Sengupta R, Richter M, Dorsey JA, Kubicek S, Opravil S, Jenuwein T, and Berger SL. (2006) Repression of p53 activity by Smyd2-mediated methylation. Nature 444:629-32.
• Huang J, Sengupta R, Espejo A, Lee MG, Dorsey JA, Richter M, Opravil S, Shiekhattar R, Bedford MT, Jenuwein T, and Berger SL. (2007) p53 is regulated by the lysine demethylase LSD1. Nature, 449:105-8.
• Bungard D, Fuerth BJ, Zeng PY, Faubert B, Viollet B, Mass N, Carling D, Thompson CB, Jones RG and Berger SL. (2010) Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science, 329: 1201-5.
• Zhu J, Sammons MA, Donahue G, Dou Z, Vedadi M, Getlik M, Barsyte-Lovejoy D, Al-Awar R, Katona BW, Shilatifard A, Huang J Hua X, Arrowsmith CH, and Berger SL. (2015) Prevalent p53 gain-of-function mutants co-opt epigenetic pathways to drive cancer growth. Nature, in press.

Discovery of chromatin mechanisms controlling aging and senescence in yeast, worm and mammalian cells. Our work has uncovered key chromatin changes that are involved in aging and cellular senescence. Our findings indicate potential epigenetic therapeutics to ameliorate age-associated disease.

• Dang W, Steffen KK, Perry R, Dorsey J, Johnson FB, Shilatifard A, Kaeberlein M, Kennedy BK, and Berger SL. (2009) Histone H4 lysine-16 acetylation regulates cellular lifespan. Nature 459:802-7.
• Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K, Aggarwala V, Cruickshanks HA, Rai TS, McBryan T, Gregory BD, Adams PD, Berger SL. (2013) Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes & Development 27:1787-99.
• Dang W, Sutphin G, Dorsey J, Otte G, Cao, K, Perry R, Wanat J, Gregory B, Vermeulen M, Shiekhattar R, Johnson, FB, Kennedy BK, Kaerberlein M, and Berger SL. (2014) Inactivation of yeast Isw2 chromatin remodeling enzyme mimics longevity effect of calorie restriction via induction of genotoxic stress response pathways. Cell Metabolism, 19:952-66.
• Sen P, Dang W, Dorsey J, Donahue G, Ciao K, Dai J, Perry R, Lee JY, Wagner J, Gregory B, Kaeberlein M, Kennedy BK, Boeke J, and Berger SL. (2015) H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes & Development, in press.

Discovery of chromatin mechanisms controlling gametogenesis in yeast and mammals. We have investigated chromatin mechanisms governing the profound restructuring and compaction of chromatin during gametogenesis (sporulation in yeast and spermatogenesis in mammals). Our work has revealed novel mechanisms and chromatin enzymes, and has showed that certain chromatin changes are conserved from yeast to mouse.

• Krishnamoorthy T, Chen X, Govin J, Cheung WL, Dorsey J, Schindler K, Winter E, Allis CD, Khochbin S, Fuller MT, Berger SL. (2006) Phosphorylation of histone H4 Ser1 regulates sporulation in yeast and is conserved in fly and mouse spermatogenesis. Genes & Development 20:2580-92.
• Govin J, Schug J, Krishnamoorthy T, Dorsey J, Khochbin S, Berger SL. (2010) Genome-wide mapping of H4 Ser-1 phosphorylation during sporulation in cerevisiae. Nucleic Acids Research, 38:4599-606.
• Govin J, Dorsey J, Gaucher J, Rousseaux S, Khochbin S, Berger SL. (2010) Systematic screen reveals new functional dynamics of histones H3 and H4 during gametogenesis. Genes & Development, 24:1772-86.
• Bryant JM, Donahue G, Wang X, Meyer-Ficca M, Luense LJ, Weller AH, Bartolomei MS, Blobel GA, Meyer RG, Garcia BA, Berger SL. (2015) Characterization of BRD4 during mammalian postmeiotic sperm development. Mol Cell Biol. 35:1433-48.

Demonstration of chromatin mechanisms controlling organismal behavior – ant eusociality.  We have pioneered investigation of eusocial ant caste-specific behavior as organismal-level chromatin regulation. Our results indicate a crucial role of histone modifications in altering brain function to dictate behavior.

• Bonasio R, Zhang G, Ye C, Mutti NS, Fang X, Qin N, Donahue G, Yang P, Li Q, Li C, Zhang P, Huang Z, *Berger SL, *Reinberg D, *Wang J, *Liebig J (2010) Genomic comparison of the ants Camponotus floridanus and Harpegnathos saltator. Science 329: 1068-71. * co-corresponding authors.
• Bonasio R, Li Q, Lian J, Mutti NS, Jin L, Zhao H, Zhang P, Wen P, Xiang H, Ding Y, Jin Z, Shen SS, Wang Z, Wang W, Wang J, Berger SL, Liebig J, Zhang G, Reinberg D. (2012) Genome-wide and Caste-Specific DNA Methylomes of the Ants Camponotus floridanus and Harpegnathos saltator. Current Biology, 22:1755-64.
• Simola DF, Wissler L, Donahue G, Waterhouse RM, Helmkampf M, Roux J, Nygaard S, Glastad KM, Hagen DE, Viljakainen L, Reese JT, Hunt BG, Graur D, Elhaik E, Kriventseva EV, Wen J, Parker BJ, Cash E, Privman E, Childers CP, Muñoz-Torres MC, Boomsma JJ, Bornberg-Bauer E, Currie CR, Elsik CG, Suen G, Goodisman MA, Keller L, Liebig J, Rawls A, Reinberg D, Smith CD, Smith CR, Tsutsui N, Wurm Y, Zdobnov EM, Berger SL, Gadau J. (2013) Social insect genomes exhibit dramatic evolution in gene composition and regulation while preserving regulatory features linked to sociality. Genome Research 23:1235-47.
• Simola DF, Ye C, Mutti N, Dolezal K, Bonasio R, Liebig J, Reinberg D, Berger SL. (2013) A chromatin link to caste identity in the carpenter ant Camponotus floridanus. Genome Research, 23:486