Fellows' research: Telomeres remotely control gene expression and epigenetics across the genome


26 Dec 2018

Fellows' research: Telomeres remotely control gene expression and epigenetics across the genome

 

Dr. Shantanu Chowdhury, Senior Fellow

CSIR-IGIB, New Delhi

Our recently concluded study, published in PLoS Genetics, shows how the size of Telomeres, structures found on the end of our chromosomes, can control the expression of genes and epigenetics across our genome.

Somewhat like the tiny cap-like clasps at the end of shoelaces, the ends of our chromosome are covered by protective DNA-protein structures called telomeres. Knowledge of how telomeres work has increased in leaps and bounds over the years. The mechanistic 'nuts-and-bolts' understanding of this shows that the telomeric-influence spreads to adjacent regions called sub-telomeres. And, mostly, that was it. What was the effect of telomeres on the rest of the vast genome? This somehow remained poorly understood. Intrigued by this we got busy with many questions and found some plausible answers. 

Telomeres influence the expression of genes that are 'miles' away in the genome

One of the first observations was that the expression of many genes spread across the genome and far from telomeres was dependent on telomeres (actually, the length of telomeres). Experiments were conducted in cells where the length of telomeres was artificially increased in both, normal and cancerous human cells, grown in our lab. These were exciting results for many reasons. Primarily because though earlier, researchers had observed the effect of telomeres on the expression of few genes, these were without exception within the extended telomeres or sub-telomeric regions.

A long known telomere-binding protein is found DNA-bound at regions remote from telomeres, and the association is telomere-sensitive

Findings in 2011 showing that the Telomeric Repeat Binding Factor 2 (TRF2), which binds to telomeres and recruits various factors and enzymes that are important for telomere maintenance and protection, has homes outside telomeres made us ponder: What happens to TRF2 occupancy outside telomeres when telomeres become long or short?

Our results show TRF2 occupancy at extra-telomeric sites was clearly 'talking' to telomeres. Short telomeres made TRF2 look for binding sites outside telomeres and vice-versa. In other words, extra-telomeric TRF2 occupancy at remote sites depended on telomere size.

 Moreover, telomere-sensitive expression of genes was a result of TRF2 binding to promoters outside telomeres.

Epigenetic state of many promoters is telomere-sensitive

We took another step, but with caution. Epigenetics—broadly, how a particular region of the chromosome is packaged—is known to impact the expression of genes.

Earlier, we had reported that TRF2 recruits proteins that modify the local epigenetic state of the p21 promoter (Hussain et al., 2017). Now, we questioned the epigenetic state of 20 other TRF2-bound promoters.

Indeed, TRF2 occupancy influenced local epigenetics. Again, this was sensitive to telomeres because TRF2 came on or off depending on whether telomeres were short/long. 

While these findings help explain telomere-dependent gene expression at remote sites and implicate even larger issues, for instance, chromatin packaging, we are aware that many more intricacies remain to be understood. Therefore, this might just be the beginning of understanding the influence of telomeres on the genome.

Reference:

Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends. Mukherjee AK, Sharma S, Sengupta S, Saha D, Kumar P, Hussain T, Srivastava V, Roy SD, Shay JW, Chowdhury S. PLoS Genetics. November 2018. 

Banner Credits: Shalu Sharma (published in PLoS Genetics. 2018 Nov 15;14(11):e1007782)