# Regulation of human telomerase

> **NIH NIH R35** · WASHINGTON STATE UNIVERSITY · 2024 · $382,500

## Abstract

Abstract
 Our long-term goal is to decipher the molecular mechanisms of telomerase regulation and telomere
homeostasis during development. Telomerase elongates telomeres to compensate for their loss during cell
proliferation. Its regulation is critical for human aging and susceptibilities to cancer and many age-related
degenerative diseases. The TERT gene, encoding the human telomerase reverse transcriptase, is regulated
primarily at the level of transcription. It is highly expressed in pluripotent stem cells, but stringently repressed in
most somatic cells. Recent progresses on telomerase regulation in cancer cells have greatly improved our
understanding of TERT gene activation during cancer development. However, the mechanisms of its repression
in most differentiated cells and expression in certain somatic cells remain to be elucidated. Regulation of
transcription during development and differentiation often involves distal elements and chromatin reorganization.
We previously reported that the endogenous TERT gene was embedded in a condensed chromatin domain and
stringently repressed in a histone deacetylase-dependent manner in somatic cells. To identify distal regulatory
sequences required for establishing the repressive chromatin of the TERT locus and to understand its regulation
in vivo, our laboratory has developed two innovative technical platforms in the past decade. The first is
recombinase-mediated BAC targeting or RMBT method, for targeted integration of single-copy BAC reporters
into specified chromosomal sites. This technique, together with the new CRISPR-mediated gene editing, enables
us to study distal regulatory elements of the TERT gene in their genomic contexts. Consequently, we have
discovered that a polymorphic tandem DNA repeat in intron 2 (VNTR2-1) functions as an enhancer for TERT
transcription. In addition, we have engineered a humanized mTert allele (hmTert) for studying human-specific
telomerase regulation in mice. In the next funding period, we plan to use these tools and focus on the following
three directions: (1) Identify transcription factors that regulate TERT gene via VNTR2-1; (2) Identify key distal
regulatory elements responsible for TERT repression; and (3) Study the roles of these distal elements in
regulating telomere homeostasis in vivo using our mouse model with humanized telomeres. In short, using our
unique tools, we will address some of the fundamental mechanisms critical to telomerase regulation and
telomere homeostasis in humans, and ultimately telomere-associated human diseases.

## Key facts

- **NIH application ID:** 10833539
- **Project number:** 5R35GM149529-02
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** JIYUE ZHU
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $382,500
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833539

## Citation

> US National Institutes of Health, RePORTER application 10833539, Regulation of human telomerase (5R35GM149529-02). Retrieved via AI Analytics 2026-06-26 from https://api.ai-analytics.org/grant/nih/10833539. Licensed CC0.

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