Dataset Information

A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development.

ABSTRACT: Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue. To demonstrate the importance of such regions in craniofacial development and disease, we focused on an ~600 kb noncoding region located between NPVF and NFE2L3. We identified long range interactions with this region in both human and mouse embryonic craniofacial tissue with the anterior portion of the HOXA gene cluster. Mice lacking this superenhancer exhibit perinatal lethality, and present with highly penetrant skull defects and orofacial clefts phenocopying Hoxa2-/- mice. Moreover, we identified two cases of de novo copy number changes of the superenhancer in humans both with severe craniofacial abnormalities. This evidence suggests we have identified a critical noncoding locus control region that specifically regulates anterior HOXA genes and copy number changes are pathogenic in human patients.

SUBMITTER: Wilderman A

PROVIDER: S-EPMC10762089 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development.

Wilderman Andrea A D'haene Eva E Baetens Machteld M Yankee Tara N TN Winchester Emma Wentworth EW Glidden Nicole N Roets Ellen E Van Dorpe Jo J Janssens Sandra S Miller Danny E DE Galey Miranda M Brown Kari M KM Stottmann Rolf W RW Vergult Sarah S Weaver K Nicole KN Brugmann Samantha A SA Cox Timothy C TC Cotney Justin J

Nature communications 20240102 1

Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue ...[more]

PMID: 38167838

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Project description:ObjectivesPrior injury to the knee, particularly anterior cruciate ligament (ACL) injury, is known to predispose one to premature osteoarthritis (OA). The study sought to explore if there was a biomechanical rationale for this process by investigating changes in external knee moments between people with a history of ACL injury and uninjured participants during walking: (1) on different surface inclines and (2) at different speeds. In addition we assessed functional differences between the groups.Participants12 participants who had undergone ACL reconstruction (ACLR) and 12 volunteers with no history of knee trauma or injury were recruited into this study. Peak knee flexion and adduction moments were assessed during flat (normal and slow speed), uphill and downhill walking using an inclined walkway with an embedded Kistler Force plate, and a ten-camera Vicon motion capture system. Knee injury and Osteoarthritis Outcome Score (KOOS) was used to assess function. Multivariate analysis of variance (MANOVA) was used to examine statistical differences in gait and KOOS outcomes.ResultsNo significant difference was observed in the peak knee adduction moment between ACLR and control participants, however, in further analysis, MANOVA revealed that ACLR participants with an additional meniscal tear or collateral ligament damage (7 participants) had a significantly higher adduction moment (0.33±0.12 Nm/kg m) when compared with those with isolated ACLR (5 participants, 0.1±0.057 Nm/kg m) during gait at their normal speed (p<0.05). A similar (non-significant) trend was seen during slow, uphill and downhill gait.ConclusionsParticipants with an isolated ACLR had a reduced adductor moment rather an increased moment, thus questioning prior theories on OA development. In contrast, those participants who had sustained associated trauma to other key knee structures were observed to have an increased adduction moment. Additional injury concurrent with an ACL rupture may lead to a higher predisposition to osteoarthritis than isolated ACL deficiency alone.

Dataset Information

A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development.

Publications

A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development.

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