Alternative splicing is a developmental switch for hTERT expression

Alex Penev, Andrew Bazley, Michael Shen, Jef D. Boeke, Sharon A. Savage, Agnel Sfeir

    Research output: Contribution to journalArticlepeer-review

    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.

    Original languageEnglish (US)
    Pages (from-to)2349-2360.e6
    JournalMolecular Cell
    Volume81
    Issue number11
    DOIs
    StatePublished - Jun 3 2021

    Keywords

    • SON
    • alternative splicing
    • hTERT
    • pluripotent cells
    • telomerase
    • telomeres

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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