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Hypoxia induces transcription of DOT1L in articular cartilage to protect against osteoarthritis

Abstract : Osteoarthritis is the most prevalent joint disease worldwide and a leading source of pain and disability. To date, this disease lacks curative treatment as underlying molecular mechanisms remain largely unknown. The histone methyltransferase DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human and mouse osteoarthritic joints. Thus, restoring DOT1L function seems to be critical to preserve joint health. However, DOT1L-regulating molecules and networks remain elusive, in the joint and beyond. Here, we identify transcription factors and networks that regulate DOT1L gene expression using a novel bioinformatics pipeline. Thereby, we unravel an undiscovered link between the hypoxia pathway and DOT1L. We provide unprecedented evidence that hypoxia enhances DOT1L expression and H3K79 methylation via hypoxia-inducible factor-1 alpha (HIF-1α). Importantly, we demonstrate that DOT1L contributes to the protective effects of hypoxia in articular cartilage and osteoarthritis. Intra-articular treatment with a selective hypoxia mimetic in mice after surgical induction of osteoarthritis restores DOT1L function and stalls disease progression. Collectively, our data unravel a novel molecular mechanism that protects against osteoarthritis with hypoxia inducing DOT1L transcription in cartilage. Local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis.
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Preprints, Working Papers, ...
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Contributor : Frédéric Cailotto Connect in order to contact the contributor
Submitted on : Friday, October 15, 2021 - 11:05:38 AM
Last modification on : Thursday, November 4, 2021 - 3:08:54 PM


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Astrid de Roover, Ana Escribano, Frederique Cornelis, Chahrazad Cherifi, Leire Casas-Fraile, et al.. Hypoxia induces transcription of DOT1L in articular cartilage to protect against osteoarthritis. 2021. ⟨hal-03379813⟩



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