HDAC9 structural variants disrupting TWIST1 transcriptional regulation lead to craniofacial and limb malformations.

Autor:	Hirsch N; Department of Life Sciences, Faculty of Natural Sciences, The Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.; Center of Evolutionary Genomics and Medicine, The Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel., Dahan I; Department of Life Sciences, Faculty of Natural Sciences, The Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.; Center of Evolutionary Genomics and Medicine, The Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel., D'haene E; Center for Medical Genetics, Ghent University, 9000, Ghent, Belgium., Avni M; Department of Life Sciences, Faculty of Natural Sciences, The Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.; Center of Evolutionary Genomics and Medicine, The Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel., Vergult S; Center for Medical Genetics, Ghent University, 9000, Ghent, Belgium., Vidal-García M; Department of Cell Biology and Anatomy, Alberta Children's Hospital Research Institute, University of Calgary, T2N 1N4, Calgary, Alberta, Canada., Magini P; U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy., Graziano C; U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy., Severi G; U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy., Bonora E; U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy.; Department of Medical and Surgical Sciences, University of Bologna, 40126, Bologna, Italy., Nardone AM; Medical Genetics Unit, Policlinico Tor Vergata University Hospital, 00133, Rome, Italy., Brancati F; Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100, L'Aquila, Italy.; Human Functional Genomics Laboratory, San Raffaele Pisana, 00167, Rome, Italy., Fernández-Jaén A; Department of Pediatrics and Neurology, Hospital Universitario Quirónsalud, School of Medicine, Universidad Europea de Madrid, 28223, Madrid, Spain., Rory OJ; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA., Hallgrímsson B; Department of Cell Biology and Anatomy, Alberta Children's Hospital Research Institute, University of Calgary, T2N 1N4, Calgary, Alberta, Canada., Birnbaum RY; Department of Life Sciences, Faculty of Natural Sciences, The Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.; Center of Evolutionary Genomics and Medicine, The Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
Jazyk:	angličtina
Zdroj:	Genome research [Genome Res] 2022 Jul; Vol. 32 (7), pp. 1242-1253. Date of Electronic Publication: 2022 Jun 16.
DOI:	10.1101/gr.276196.121
Abstrakt:	Structural variants (SVs) can affect protein-coding sequences as well as gene regulatory elements. However, SVs disrupting protein-coding sequences that also function as cis -regulatory elements remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the histone deacetylase 9 (HDAC9 ) protein-coding sequence are associated with disruption of TWIST1 regulatory elements that reside within the HDAC9 sequence. Based on SVs within the HDAC9 - TWIST1 locus, we defined the 3'- HDAC9 sequence as a critical TWIST1 regulatory region, encompassing craniofacial TWIST1 enhancers and CTCF sites. Deletions of either Twist1 enhancers (eTw5-7 Δ/Δ ) or CTCF site (CTCF-5 Δ/Δ ) within the Hdac9 protein-coding sequence led to decreased Twist1 expression and altered anterior/posterior limb expression patterns of SHH pathway genes. This decreased Twist1 expression results in a smaller sized and asymmetric skull and polydactyly that resembles Twist1 +/- mouse phenotype. Chromatin conformation analysis revealed that the Twist1 promoter interacts with Hdac9 sequences that encompass Twist1 enhancers and a CTCF site, and that interactions depended on the presence of both regulatory regions. Finally, a large inversion of the entire Hdac9 sequence ( Hdac9 INV/+ ) in mice that does not disrupt Hdac9 expression but repositions Twist1 regulatory elements showed decreased Twist1 expression and led to a craniosynostosis-like phenotype and polydactyly. Thus, our study elucidates essential components of TWIST1 transcriptional machinery that reside within the HDAC9 sequence. It suggests that SVs encompassing protein-coding sequences could lead to a phenotype that is not attributed to its protein function but rather to a disruption of the transcriptional regulation of a nearby gene. (© 2022 Hirsch et al.; Published by Cold Spring Harbor Laboratory Press.)
Databáze:	MEDLINE
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