Journal article
DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
Science advances, Vol.9(7), eabq7744
02/17/2023
DOI: 10.1126/sciadv.abq7744
PMCID: PMC9937577
PMID: 36800423
Abstract
mutations cause congenital arhinia (absent nose) and a muscular dystrophy called FSHD2. In FSHD2, loss of SMCHD1 repressive activity causes expression of double homeobox 4 (DUX4) in muscle tissue, where it is toxic. Studies of arhinia patients suggest a primary defect in nasal placode cells (human nose progenitors). Here, we show that upon SMCHD1 ablation, DUX4 becomes derepressed in H9 human embryonic stem cells (hESCs) as they differentiate toward a placode cell fate, triggering cell death. Arhinia and FSHD2 patient-derived induced pluripotent stem cells (iPSCs) express DUX4 when converted to placode cells and demonstrate variable degrees of cell death, suggesting an environmental disease modifier. HSV-1 may be one such modifier as herpesvirus infection amplifies DUX4 expression in SMCHD1 KO hESC and patient iPSC. These studies suggest that arhinia, like FSHD2, is due to compromised SMCHD1 repressive activity in a cell-specific context and provide evidence for an environmental modifier.
Details
- Title: Subtitle
- DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
- Creators
- Kaoru Inoue - National Institute of Environmental Health SciencesHamed Bostan - National Institute of Environmental Health SciencesMaKenna R Browne - National Institute of Environmental Health SciencesOwen F Bevis - National Institute of Environmental Health SciencesCarl D Bortner - National Institute of Environmental Health SciencesSteven A Moore - University of IowaAaron A Stence - University of Iowa Hospitals and Clinics, Iowa City, IA, USANegin P Martin - National Institute of Environmental Health SciencesShih-Heng Chen - National Institute of Environmental Health SciencesAdam B Burkholder - National Institute of Environmental Health SciencesJian-Liang Li - National Institute of Environmental Health SciencesNatalie D Shaw - National Institute of Environmental Health Sciences
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.9(7), eabq7744
- DOI
- 10.1126/sciadv.abq7744
- PMID
- 36800423
- PMCID
- PMC9937577
- NLM abbreviation
- Sci Adv
- eISSN
- 2375-2548
- Language
- English
- Date published
- 02/17/2023
- Academic Unit
- Pathology
- Record Identifier
- 9984367186202771
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