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

ABSTRACT: 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 th

SUBMITTER: Hirsch N 

PROVIDER: S-EPMC9341515 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature