Understanding the three-dimensional (3D) genome organization underlying senescence-associated transcriptional regulation remains a major obstacle to overcome. Cellular senescence is accompanied by! radical changes in transcription. For instance, senescent cells are associated with the dramatic upregulation of genes encoding secreted factors such as pro-inflammatory cytokines and chemokines, termed the senescence-associated secretory phenotype (SASP). Moreover, collaborative studies by the P01 team reveal that senescence is characterized by aberrant cryptic transcription, which causes transcription infidelity. Thus, it is critical to understand the 3D genomic basis of transcriptional regulation in senescent cells. Accordingly, the overall goal of this application is to determine 3D genomic basis of transcriptional regulation during senescence. CAPH2 is the regulatory subunit of the condensin II complex. Condensin II is implicated in organizing 3D genomic events ranging from enhancer-promoter contacts to forming topologically associating domains (TADs) to coordinate gene transcription in interphase cells. Notably, senescent cells are often associated with dramatic chromatin structure reorganization. Our preliminary data suggest that CAPH2 orchestrates changes in gene transcription by driving the 3D genome rearrangement during senescence. HMGB2 is a chromatin architecture protein that binds to DNA without sequence specificity. HMGB2 facilitates expression of its target genes by allowing for loop formation. Our published work shows that HMGB2?s redistribution to SASP gene loci promotes their expression by preventing the spreading of heterochromatin. Our unpublished data indicate that HMGB2 interacts with CAPH2 in senescent cells. Both HMGB2 and CAPH2 are associated with SASP gene loci. Our central hypothesis is that CAPH2 organizes the 3D genomic structure to regulate transcription during senescence. We also hypothesize that the CAPH2/HMGB2 complex forms the 3D genomic basis of the SASP.
Three specific aims are proposed:
Aim 1 will investigate the 3D genome structure basis of transcriptional infidelity during cellular senescence;
Aim 2 will characterize the interaction between HMGB2 and condensin II complex;
Aim 3 will determine the mechanism by which the CAPH2/HMGB2 complex regulates SASP. This application is highly innovative because this is the first study to explore 3D genomic basis that orchestrates gene transcription during senescence. Thus, our studies are paradigm-shifting in their potential to elucidate the 3D genomic basis of transcriptional reprogramming during senescence. The proposed studies are of high impact because these newly gained insights may ultimately allow for the development of rationale strategies to limit the detrimental side effects of senescence and consequently promotes healthy aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG031862-11
Application #
9491067
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Berson, Amit; Sartoris, Ashley; Nativio, Raffaella et al. (2017) TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol 27:3579-3590.e6
Bonini, Nancy M; Berger, Shelley L (2017) The Sustained Impact of Model Organisms-in Genetics and Epigenetics. Genetics 205:1-4
Mews, Philipp; Donahue, Greg; Drake, Adam M et al. (2017) Acetyl-CoA synthetase regulates histone acetylation and hippocampal memory. Nature 546:381-386
Ricketts, M Daniel; Marmorstein, Ronen (2017) A Molecular Prospective for HIRA Complex Assembly and H3.3-Specific Histone Chaperone Function. J Mol Biol 429:1924-1933
Simithy, Johayra; Sidoli, Simone; Yuan, Zuo-Fei et al. (2017) Characterization of histone acylations links chromatin modifications with metabolism. Nat Commun 8:1141
Yang, Ting-Lin B; Chen, Qijun; Deng, Jennifer T et al. (2017) Mutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche. Nat Commun 8:14766
Feng, Zijie; Wang, Lei; Sun, Yanmei et al. (2017) Menin and Daxx Interact to Suppress Neuroendocrine Tumors through Epigenetic Control of the Membrane Metallo-Endopeptidase. Cancer Res 77:401-411
Vizioli, Maria Grazia; Adams, Peter D (2016) Senescence Can Be BETter without the SASP? Cancer Discov 6:576-8
Sen, Payel; Shah, Parisha P; Nativio, Raffaella et al. (2016) Epigenetic Mechanisms of Longevity and Aging. Cell 166:822-839
Pchelintsev, Nikolay A; Adams, Peter D; Nelson, David M (2016) Critical Parameters for Efficient Sonication and Improved Chromatin Immunoprecipitation of High Molecular Weight Proteins. PLoS One 11:e0148023

Showing the most recent 10 out of 76 publications