Journal
DEVELOPMENTAL CELL
Volume 46, Issue 6, Pages 794-+Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2018.07.024
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Funding
- AMED-CREST from AMED [JP15gm0410001, JP17gm0810008]
- Naito Foundation
- Daiichi Sankyo Foundation of Life Science
- JSPS KAKENHI [26113008, 15H02560, 15K15544]
- National Institutes of Health [AR050631, AR065379]
- Japan Orthopaedics and Traumatology Research Foundation, Inc. [295]
- Grants-in-Aid for Scientific Research [15K15544, 15H02560, 26113008] Funding Source: KAKEN
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SRY-box 9 (SOX9) is a master transcription factor that regulates cartilage development. SOX9 haploinsufficiency resulting from breakpoints in a similar to 1-Mb region upstreamofSOX9wasreported in acampomelic campomelic dysplasia (ACD) patients, suggesting that essential enhancer regions of SOX9 for cartilage development are located in this long non-coding sequence. However, the cis-acting enhancer region regulating cartilage-specific SOX9 expression remains to be identified. To identify distant cartilage Sox9 enhancers, we utilized the combination of multiple CRISPR/Cas9 technologies including enrichment of the promoter-enhancer complex followed by next-generation sequencing and mass spectrometry (MS), SIN3A-dCas9-mediated epigenetic silencing, and generation of enhancer deletion mice. As a result, we could identify a critical far-upstream cis-element and Stat3 as a trans-acting factor, regulating cartilage-specific Sox9 expression and subsequent skeletal development. Our strategy could facilitate definitive ACD diagnosis and should be useful to reveal the detailed chromatin conformation and regulation.
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