PROJECT SUMMARY/ABSTRACT
Telomerase reactivation is a fundamental event in the genesis of nearly every human cancer. Although
transcriptionally silent in differentiated adult cells, its catalytic component telomerase reverse transcriptase
(TERT) is expressed in over 80% of human cancers. Despite the recent discovery of reactivating TERT
promoter mutations, very little is known about mechanisms leading to the reactivation of telomerase in human
cancer. This proposal aims to determine the underlying molecular mechanisms regulating TERT expression in
cancer. Dr. Barthel has previously shown that methylation of a region in the TERT promoter was associated
with increased transcription. Here, he will functionally resolve that DNA methylation is responsible for
reactivating telomerase in cancer development (Aim 1). This Aim uses epigenetic editing to measure the
impact of manipulating DNA methylation on telomerase activity. Furthermore, he will assess molecular
mechanisms that are affected by methylation at the TERT promoter (Aim 2). He will determine whether
chromatin conformation and transcription factor (TF) binding are regulated via methylation. Finally, he will
identify what changes in DNA methylation, TF binding and chromatin conformation are associated with
telomerase reactivation in cancer development (Aim 3). Collectively, the proposed studies will establish the
role of methylation in reactivating telomerase in cancer and provide insights into the nature of its spontaneous
reactivation. The long-term goal of Dr. Barthel is to identify vulnerabilities of telomerase reactivation during
cancer development. Over the course of this award Dr. Barthel will be supported by his primary mentor, Dr.
Roel Verhaak, a renowned computational biologist with a remarkable track record studying the molecular
biology of cancer. His co-mentor, Dr. Albert Cheng has pioneered innovative genetic engineering technologies.
In addition, Dr. Barthel has assembled an advisory committee that includes: Dr. Jerry Shay, a leader on
telomeres and telomerase in cancer; Dr. Yijun Ruan, an expert on three-dimensional chromatin conformation;
and Dr. Suneet Agarwal, who uses induced pluripotent stem cells to study telomere disease. Together, this
multidisciplinary team will enable Dr. Barthel to successfully execute the proposed experiments and advance
his professional development plan to facilitate his transition to an independent academic position. Pillars of the
proposed research skills training program include advanced training in genetic engineering, chromatin
conformation analysis and induced pluripotency. Professional development will feature key elements including
mentorship, grant writing and laboratory management. Work towards the proposed project will primarily be
conducted at The Jackson Laboratory for Genomic Medicine, which offers all the state-of-the art facilities
required for the successful completion of the Aims in addition to a collegial scientific environment. Given his
detailed research plan, excellent advisory committee and comprehensive training plan it is expected that Dr.
Barthel will quickly transition to an independent faculty position through this award.