Cancer and Aging, and Stem Cell Biology
Research SummaryTelomerase expression and telomere maintenance are required for limitless proliferation of immortal cells, including pluripotent stem cells and the majority of cancer cells. Human telomerase is silenced during cell differentiation and consequently, somatic cells undergo finite numbers of cell division before senescing, due to their limited telomere reservoirs. On the other hand, telomerase is activated during the progression of many types of human cancers. Our current research projects are focused on studying the chromatin/epigenetic mechanisms of telomerase gene regulation using models of human somatic cells, pluripotent stem cells (PSCs, e.g. ESCs), induced pluripotent stem cells (iPSCs), and transgenic mice. Our goal is to dissect the critical steps and genetic elements involved in hTERT repression during cell differentiation and its activation during tumorigenesis and nuclear reprogramming. These mechanisms are also likely to contribute to human aging.
Because telomerase activity is required for proliferation and survival of cancer cells, telomerase inhibition is an important therapeutic anti-cancer strategy. Therefore, we will also identify small molecules that regulate telomerase activity in human cells.
Research PublicationsCheng, D., Wang, S., Jia, W., Zhao, Y., Zhang, F., Kang, J., and J. Zhu. (2017) Regulation of human and mouse telomerase genes by genomic contexts and transcription factors during embryonic stem cell differentiation. Scientific Reports 7(1):16444
Cheng, D., Zhao, Y., Wang, S., Zhang, F., Russo, M., McMahon, S.B., and J. Zhu. (2016) Repression of telomerase gene promoter requires human-specific genomic context and is mediated by multiple HDAC1-containing corepressor complexes. The FASEB Journal. 31(3):1165-1178.
Cheng, D., Zhao, Y., Wang, S., Jia, W., Kang, J., and Zhu, J. (2015) Human Telomerase Reverse Transcriptase (hTERT) Transcription Requires Sp1/Sp3 Binding to the Promoter and a Permissive Chromatin Environment. J. Biol. Chem. 290(50):30193-203.
Ma, Y., Wang, S., Zhao, Y., Hao, S., Spector, DJ., Lim, B., Zheng, S., El-Deiry, WS., and Zhu, J. (2015) A combinatory strategy for circulating tumor cell detection using microfilter capturing and adenoviral imaging. Mocular Cancer Therapeutics, 14(3):835-43.
Zhao, Y., Cheng, D., Wang, S., and Zhu, J. (2014) Dual roles of c-Myc in the regulation of hTERT gene. Nucleic Acids Research, 42(16):10385-98.
Jia, W., Wang, S., Horner, J.W., Wang, N., Wang, H., Gunther, E.J., DePinho, R.A., and Zhu, J. (2011) A BAC transgenic reporter recapitulates in vivo regulation of human telomerase reverse transcriptase in development and tumorigenesis. The FASEB Journal. 25:979-89.
Wang, S., Hu, C., Zhao, Y., and J. Zhu. (2010) Distinct and Temporal Roles of Nucleosomal Remodeling and Histone Deacetylation in the Repression of hTERT Gene. Molecular Biology of the Cell. Vol. 21:821-832.
Matthew, R., Jia, W., Sharma, A., Zhao, Y., Clarke, L.E., Cheng, X., Wang, H., Salli, U., Vrana, K.E., Robertson, G.P., Zhu, J., and S. Wang. (2010) Robust activation of the human but not mouse telomerase gene during the induction of pluripotency. The FASEB Journal. 24:2702-2715.
Zhao, Y., Wang, S., Popova, EV., Grigoryev, SA., and J. Zhu. (2009) Rearrangement of Upstream Sequences of the hTERT Gene during Cellular Immortalization. Gene, Chromosomes and Cancer. 48:963-974.