TY - JOUR
T1 - Identification of the hyaluronic acid pathway as a therapeutic target for facioscapulohumeral muscular dystrophy
AU - DeSimone, Alec M.
AU - Leszyk, John
AU - Wagner, Kathryn
AU - Emerson, Charles P.
N1 - Funding Information:
This work was supported by the FSH Society grant FSHS-82015-05 to A.M.D. and a travel grant to A.M.D. from the FSH Society Ed and Betty Schechter Memorial Research Fund and by the Wellstone Center for FSH research and NIH/National Institute of Child Health and Human Development grant U54HD0060848 to C.P.E.
Publisher Copyright:
Copyright © 2019 The Authors, some rights reserved.
PY - 2019/12/11
Y1 - 2019/12/11
N2 - Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic derepression of the germline/embryonic transcription factor DUX4 in skeletal muscle. However, the etiology of muscle pathology is not fully understood, as DUX4 misexpression is not tightly correlated with disease severity. Using a DUX4-inducible cell model, we show that multiple DUX4-induced molecular pathologies that have been observed in patient-derived disease models are mediated by the signaling molecule hyaluronic acid (HA), which accumulates following DUX4 induction. These pathologies include formation of RNA granules, FUS aggregation, DNA damage, caspase activation, and cell death. We also observe previously unidentified pathologies including mislocalization of mitochondria and the DUX4- and HA-binding protein C1QBP. These pathologies are prevented by 4-methylumbelliferone, an inhibitor of HA biosynthesis. Critically, 4-methylumbelliferone does not disrupt DUX4-C1QBP binding and has only a limited effect on DUX4 transcriptional activity, establishing that HA signaling has a central function in pathology and is a target for FSHD therapeutics.
AB - Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic derepression of the germline/embryonic transcription factor DUX4 in skeletal muscle. However, the etiology of muscle pathology is not fully understood, as DUX4 misexpression is not tightly correlated with disease severity. Using a DUX4-inducible cell model, we show that multiple DUX4-induced molecular pathologies that have been observed in patient-derived disease models are mediated by the signaling molecule hyaluronic acid (HA), which accumulates following DUX4 induction. These pathologies include formation of RNA granules, FUS aggregation, DNA damage, caspase activation, and cell death. We also observe previously unidentified pathologies including mislocalization of mitochondria and the DUX4- and HA-binding protein C1QBP. These pathologies are prevented by 4-methylumbelliferone, an inhibitor of HA biosynthesis. Critically, 4-methylumbelliferone does not disrupt DUX4-C1QBP binding and has only a limited effect on DUX4 transcriptional activity, establishing that HA signaling has a central function in pathology and is a target for FSHD therapeutics.
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U2 - 10.1126/sciadv.aaw7099
DO - 10.1126/sciadv.aaw7099
M3 - Article
C2 - 31844661
AN - SCOPUS:85076700392
SN - 2375-2548
VL - 5
JO - Science Advances
JF - Science Advances
IS - 12
M1 - eaaw7099
ER -