Telomeres control human telomerase (TERT) expression through non-telomeric TRF2

Area of Science:

• Cell Biology
• Genetics
• Molecular Biology

Background:

• The function of human telomerase reverse transcriptase (TERT) in maintaining telomeres is well-established.
• The reciprocal influence of telomere length (TL) on TERT regulation remains less understood.
• Investigating the mechanisms linking TL to TERT gene expression is crucial for understanding cellular aging and diseases like cancer.

Purpose of the Study:

• To elucidate the mechanism by which telomere length regulates TERT transcription.
• To identify the molecular players involved in the telomere length-dependent control of TERT.
• To explore the implications of this regulatory pathway in cellular reprogramming and disease.

Main Methods:

• Utilized engineered cell lines (fibrosarcoma, colon cancer, breast cancer) with controlled telomere elongation or shortening.
• Investigated the binding of TRF2 protein to the TERT promoter using ChIP assays.
• Assessed PRC2 complex recruitment and H3K27-trimethylation levels.
• Employed an exogenous TERT reporter assay to measure promoter activity.
• Analyzed TERT regulation during reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs).

Main Results:

• Demonstrated a direct correlation between telomere length and TERT transcriptional levels.
• Identified TRF2 binding to the TERT promoter as a key mediator, independent of telomere looping.
• Showed that TRF2 recruits the PRC2 complex to the TERT promoter, inducing H3K27-trimethylation in a TL-dependent manner.
• Observed TERT upregulation with telomere elongation and downregulation with shortening in various cell types and during iPSC reprogramming.
• TRF2 dissociation from the TERT promoter correlated with telomere elongation and TERT upregulation during iPSC generation.

Conclusions:

• Telomere length acts as a critical regulator of TERT transcription through TL-dependent TRF2 binding and PRC2 recruitment.
• This novel regulatory mechanism provides insights into the control of telomere homeostasis.
• The findings have significant implications for understanding aging, cancer development, and stem cell pluripotency.