@article{8e5bd747712442e5afd8adf1b64beec8,
title = "Alternative splicing is a developmental switch for hTERT expression",
abstract = "Telomere length control is critical for cellular lifespan and tumor suppression. Telomerase is transiently activated in the inner cell mass of the developing blastocyst to reset telomere reserves. Its silencing upon differentiation leads to gradual telomere shortening in somatic cells. Here, we report that transcriptional regulation through cis-regulatory elements only partially accounts for telomerase activation in pluripotent cells. Instead, developmental control of telomerase is primarily driven by an alternative splicing event, centered around hTERT exon 2. Skipping of exon 2 triggers hTERT mRNA decay in differentiated cells, and conversely, its retention promotes telomerase accumulation in pluripotent cells. We identify SON as a regulator of exon 2 alternative splicing and report a patient carrying a SON mutation and suffering from insufficient telomerase and short telomeres. In summary, our study highlights a critical role for hTERT alternative splicing in the developmental regulation of telomerase and implicates defective splicing in telomere biology disorders.",
keywords = "SON, alternative splicing, hTERT, pluripotent cells, telomerase, telomeres",
author = "Alex Penev and Andrew Bazley and Michael Shen and Boeke, {Jef D.} and Savage, {Sharon A.} and Agnel Sfeir",
note = "Funding Information: We thank Ashley S. Thompson for assistance with gene and variant curation and Marion Pouillard and Mike Al-Kareh for technical support. We acknowledge Eros-Lazzerini Denchi and members of the Sfeir lab for comments on the manuscript. We thank Luis Batista for sharing methods for hepatocyte differentiation. We are grateful to the patients, their families, and the referring clinicians for their valuable contributions. Lei Bu, Jerry Shay, and Maria Barna are thanked for reagents. We acknowledge the genome technology core (GTC), high throughput biology (HTB) core, Michael Cammer, and the microscopy core at the NYU School of Medicine. This work was supported in part by a grant from the NYSTEM and Irma T. Hirschl Foundation to A.S. an NIH fellowship to A.P. and an NIH grant (RM1HG009491) to J.D.B. The work in the lab of S.A.S. is supported by the intramural program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. The authors would like to dedicate this study to the memory of Woodring E. Wright. A.S. and A.P. conceived the experimental design. A.P. performed all experiments. A.B. assisted with the RNAi screen. M.S. in the lab of J.D.B. helped generate the minigene reporter plasmids. S.A.S. evaluated clinical data from the patient with SON mutation. A.S. and A.P. wrote the manuscript. All authors discussed the results and commented on the manuscript. A.S. is a co-founder, consultant, and shareholder in Repare Therapeutics. J.D.B. is a founder and director of CDI Labs, Inc. a founder of Neochromosome, Inc. a founder and scientific advisory board (SAB) member of ReOpen Diagnostics, and serves or served on the SABs of Sangamo, Inc. Modern Meadow, Inc. Sample6, Inc. and the Wyss Institute. Funding Information: We thank Ashley S. Thompson for assistance with gene and variant curation and Marion Pouillard and Mike Al-Kareh for technical support. We acknowledge Eros-Lazzerini Denchi and members of the Sfeir lab for comments on the manuscript. We thank Luis Batista for sharing methods for hepatocyte differentiation. We are grateful to the patients, their families, and the referring clinicians for their valuable contributions. Lei Bu, Jerry Shay, and Maria Barna are thanked for reagents. We acknowledge the genome technology core (GTC), high throughput biology (HTB) core, Michael Cammer, and the microscopy core at the NYU School of Medicine. This work was supported in part by a grant from the NYSTEM and Irma T. Hirschl Foundation to A.S., an NIH fellowship to A.P., and an NIH grant ( RM1HG009491 ) to J.D.B. The work in the lab of S.A.S. is supported by the intramural program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH . The authors would like to dedicate this study to the memory of Woodring E. Wright. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = jun,
day = "3",
doi = "10.1016/j.molcel.2021.03.033",
language = "English (US)",
volume = "81",
pages = "2349--2360.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "11",
}