1. Identification of transcriptional adaptors/coactivators Gcn5/Ada2/Ada3 and discovery of novel histone modifications and mechanisms in transcription and sperm genome opening
We discovered transcriptional “adaptors”, which we showed associate with DNA binding activators, a groundbreaking new model for transcriptional activation, to reveal how histone enzymatic modifiers are recruited to genes (Berger+, Cell1990, Cell1993). We revealed the importance of adaptor Gcn5 acetyltransferase activity in transcriptional activation (1998), unifying transcription and chromatin regulation. We discovered numerous novel histone modifications (PTMs), PTM cross-talk, and sequential histone PTMs in transcription, including histone phosphorylation/acetylation (2001) and ubiquitylation/deubiquitylation. We discovered (2017) that enhancer RNAs bind directly to CBP, the key metazoan acetyltransferase, to stimulate HAT activity in vitro and at enhancers in vivo. We showed (2019) that Gcn5 provides key histone acetylation to broadly open the mouse genome during spermatogenesis for extensive chromatin restructuring.
a. 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. PMCID: PMC316586
b. Lo W-S…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. PMID:111498592
c. Bose DA, Donahue G, Reinberg D, Shiekhattar R, Bonasio R, Berger SL. (2017) RNA binding to CBP stimulates histone acetylation and transcription. Cell 168,135-149. PMCID: PMC5325706.
d. Luense LJ, Donahue G, Lin-Shiao E….Bartolomei M, Berger SL. (2019) Gcn5-mediated histone acetylation governs nucleosome dynamics in spermiogenesis. Developmental Cell 51:745-758.
2. Discovery of chromatin mechanisms controlling aging and senescence
We uncovered chromatin changes involved in aging and cellular senescence, indicating broad epigenome dysregulation. These include pioneering studies that histone acetylation drives aging in yeast (2009), disrupts the nuclear laminar chromatin in mammals, and are crucial to enhancer function in aging (2019). We showed these disruptions trigger both homeostatic genomic protection and cellular damage, and discovered nuclear autophagy pathways in senescence leading to inflammation in aging and cancer (2015,2017,2020). Our findings suggest potential epigenetic therapeutics to ameliorate age-associated disease.
a. Dang W…Kaeberlein M, Kennedy BK, and Berger SL. (2009) Histone H4 lysine-16 acetylation regulates cellular lifespan. Nature 459:802-7. PMCID: PMC2702157.
b. Dou Z…Adams PD^, and Berger SL^. (2015) Autophagy mediates degradation of nuclear lamina. Nature 527:105-9. PMCID: PMC4824414. (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402-406. PMID:28976970.
c. Sen P, Lan Y…Adams PD, Schultz DC, Berger SL. (2019) Histone acetyltransferase p300 induces de novo super-enhancers to drive cellular senescence. Molecular Cell 73:684-698. PMID:30773298.
d. Xu C, Wang L…Adams PA, Ott M, Tong W, Johansen T, Dou Z^, and Berger SL^. (2020) SIRT1 is downregulated by autophagy in senescence and aging. Nature Cell Biology 22:1170-1179.
3. Demonstration of chromatin mechanisms controlling memory and behavior and relevant to aging.
Our studies in mouse brain and memory show a pivotal role of the metabolic enzyme, ACSS2, in fueling “on-site” acetyl-CoA generation on chromatin for neuronal histone acetylation and gene expression in normal memory and in alcohol-fueled addiction memory (2017/19). Our work in human Alzheimer’s disease reveals that the cognitively normal aging brain is epigenetically protected compared to the AD brain (2018/20). In other research on brain, we pioneered investigation of eusocial ant caste-specific behavior for organismal-level chromatin regulation and epigenetics, owing to the remarkable fact that female ants of distinct social castes (such as queen, soldier, and forager) share an identical genome. We sequenced the first ant genomes and then profiled the first histone modification epigenomes (2010,Science) and pioneered Crispr genetics in ants (2017,Cell). Groundbreaking results indicate a critical role of histone modifications in altering ant brain function to instruct complex social behavior; we identified a “window”, early after hatching, to behavioral reprogramming via epigenetic manipulation (2016/2020). We linked regulation of caste behavior to remarkable aging disparity.
a. Simola DF…Reinberg D^, Liebig J^, Berger SL^. (2016) Epigenetic (re)programming of caste-specific behavior in the ant C. floridanus. Science 351:aac6633. PMID: 26722000, PMCID: PMC5057185.
b. Mews, P… Berger SL. (2017) Acetyl-CoA metabolism by ACSS2 regulates neuronal histone acetylation and hippocampal memory. Nature 546,381-386. PMCID: PMC5505514. Mews P, Egervari G^…Garcia, B, Berger SL^. (2019) Alcohol metabolism contributes to brain histone acetylation. Nature 574: 717-721.
c. Glastad K, Graham RJ, Ju L, Rossler J, Brady CM, and Berger SL (2020) Epigenetic regulator CoRest controls social behavior in ants. Molecular Cell 77:338-351.
d. Nativio R, Donahue G…Johnson FB^, Bonini NM^, Berger SL^ (2018) Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nature Neuroscience 21,497-505. Nativio R, Lan Y…Garcia BA, Trojanowski JQ, Bonini NM^, Berger SL^. (2020) An integrated multi-omics approach identifies epigenetic drivers associated with Alzheimer’s disease. Nature Genetics 52:1024-1035.
- Discovery of tumor suppressor p53 factor and histone 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 and post-translational modifications of p53 (including acetylation, methylation, and demethylation, 2006/7) regulating p53 activity. Our findings propelled broad efforts in the field to discover novel acetylation and methylation of transcription factors. We showed p53 methylation is generally repressive to its function, and showed repressive p53 methylation occurring in certain cancers bearing high levels of wild type p53. We discovered novel epigenetic pathways used by wild type and mutant p53 in regulating chromatin structure/function in normal and cancer cells, such as gain-of-function p53 mutants driving transcriptional activating and growth promoting histone modifications (2015). We showed that p53 and p63 establish new enhancers during stress and development. We found a novel role of p53 in promoting target gene association with nuclear speckles for transcriptional amplification (2021).
- a. Huang J…Jenuwein T, andBerger SL. (2006) Repression of p53 activity by Smyd2-mediated methylation. Nature 444:629-32. PMID:17108971. Huang J…Jenuwein T, and Berger SL. (2007) p53 is regulated by the lysine demethylase LSD1. Nature, 449:105-8.
- Bungard D…Thompson CB, Jones RG andBerger SL. (2010) Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329: 1201-5. PMCID: PMC3922052.
- Zhu J, Sammons MA, Donahue G, Dou Z…Arrowsmith CH, andBerger SL. (2015) Gain-of-function p53 mutants co-opt epigenetic pathways to drive cancer growth. Nature 525:206-11. PMCID: PMC4568559
- Alexander KA…Belmont A, Joyce EF, Raj A, and Berger SL. (2021) p53 mediates target gene association with nuclear speckles for amplified RNA expression. Molecular Cell 81:1666-1681.
- Investigation of epigenetic mechanisms in T and CART cell exhaustion and cancer immunotherapy
We established collaborations with Carl June (pioneer of CAR T cell therapy in cancer) and John Wherry (discovered key aspects of T cell exhaustion). We investigate epigenetic regulation in patient response to immunotherapy, and controlling T cell exhaustion in mouse models.
- Pauken KE…Berger SL, and Wherry EJ. (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.Science 354,1160-1165. Khan O…Berger SL, and Wherry EJ. (2019) TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211.
- Fraietta JA…Berger SL, Bushman FD, June CH, and Melenhorst JJ. (2018) Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T-cells.Nature 555, 307-312.
- Chen Z…Berger SL, Wherry EJ, and Shi J. In vivo CRISPR screening identifies Fli1 as a transcriptional safeguard that restrains effector CD8 T cell differentiation during infection and cancer. Cell 184:1262.
- Good CR+, Kuramitsu S+, Aznar MA+…Young RM^,Berger SL^, June CH^ (2021) In vitro dysfunction model reveals the plasticity of patient CAR-T cells and identifies transcription factors whose modulation can restrain CAR-T cell exhaustion. Cell, 184:6081-6100.