Human telomeres are complex nucleoprotein structures that maintain and monitor chromosome ends to coordinate genome integrity with cellular replicative capacity. Telomere maintenance aberrations are hallmarks of human cancer, as well as the source of several inherited syndromes associated with genetic instability and stem cell failure. Telomere repeat length and telomere repeat binding factors have well- established roles in genome maintenance and signaling. On the other hand, telomeric chromatin, which extends far beyond the terminal repeats, is also required for chromosome end-protection and signaling, but the precise structures and mechanisms of human telomeric chromatin are not well understood. Here, we propose to investigate the structure and function of human telomeric chromatin in normal and pathogenic conditions, including inherited telomere maintenance disorders and cancers. We will leverage newly developed methods for mapping and analyzing genome-wide sequence data to the human subtelomeric repeats and duplicons that comprise the regions adjacent to telomere repeats. Our published and preliminary data reveal that subtelomeric chromatin regulatory factors CTCF and cohesin regulate RNA polymerase II recruitment and the expression of telomere repeat containing RNA (TERRA). We have also found that DNA damage sensing factors, including p53, bind directly within subtelomeric sequence to promote TERRA transcription in response to DNA damage and to enhance telomere DNA protection and repair. We will use functional genomics methods to build a comprehensive epigenomic map of RNA transcripts, histone modifications, DNA modification, and chromatin regulatory factor interactions with human subtelomeric DNA. We have also initiated a new collaboration to identify novel and complex histone modification patterns specifically enriched at human telomeres. We will use CRISPR genome engineering methods to investigate the functional properties of CTCF and p53 binding sites in human subtelomeres. Finally, we will determine if telomere epigenomic patterns and chromatin structures are significantly altered in human cancers and inherited disorders associated with telomere dysfunction, and how these changes may alter telomere metabolism. These studies will provide important new information on the chromatin organization and epigenetic programming of human telomeres in normal development and disease.

Public Health Relevance

Human telomeres are complex chromatin structures required for chromosome stability and frequently defective in human cancer and related disease. Telomeric chromatin has unique, but poorly defined, epigenetic features that regulate telomere function and chromosome stability. We propose to use genomic and proteomic methods to investigate telomeric chromatin in normal and pathogenic states, including proliferation stress and cancer. These studies will provide important new information on human telomere chromatin control and epigenetic programming, as well as identify new biomarkers and therapeutic targets for human diseases associated with telomere dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140652-08
Application #
9257286
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Witkin, Keren L
Project Start
2010-07-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
8
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Mawhinney, Matthew T; Liu, Runcong; Lu, Fang et al. (2018) CTCF-Induced Circular DNA Complexes Observed by Atomic Force Microscopy. J Mol Biol 430:759-776
Tutton, Stephen; Lieberman, Paul M (2017) A role for p53 in telomere protection. Mol Cell Oncol 4:e1143078
Beishline, Kate; Vladimirova, Olga; Tutton, Stephen et al. (2017) CTCF driven TERRA transcription facilitates completion of telomere DNA replication. Nat Commun 8:2114
Wang, Zhuo; Deng, Zhong; Tutton, Steve et al. (2017) The Telomeric Response to Viral Infection. Viruses 9:
McCaffrey, Jennifer; Young, Eleanor; Lassahn, Katy et al. (2017) High-throughput single-molecule telomere characterization. Genome Res 27:1904-1915
Young, Eleanor; Pastor, Steven; Rajagopalan, Ramakrishnan et al. (2017) High-throughput single-molecule mapping links subtelomeric variants and long-range haplotypes with specific telomeres. Nucleic Acids Res 45:e73
Lieberman, Paul M (2016) Retrotransposon-derived p53 binding sites enhance telomere maintenance and genome protection. Bioessays 38:943-9
Nelson, David M; Jaber-Hijazi, Farah; Cole, John J et al. (2016) Mapping H4K20me3 onto the chromatin landscape of senescent cells indicates a function in control of cell senescence and tumor suppression through preservation of genetic and epigenetic stability. Genome Biol 17:158
Wang, Zhuo; Lieberman, Paul M (2016) The crosstalk of telomere dysfunction and inflammation through cell-free TERRA containing exosomes. RNA Biol 13:690-5

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