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Integration of 3D genome architecture and local chromatin features uncovers enhancers underlying craniofacial-specific cartilage defects

ABSTRACT: Aberrations in tissue-specific enhancers underlie many developmental defects. Disrupting a distal noncoding region of the human SOX9 gene causes the Pierre Robin sequence (PRS) characterized by the undersized lower jaw. Such a craniofacial-specific defect has been previously linked to enhancers transiently active in cranial neural crest cells (CNCCs). We demonstrate the PRS region also strongly regulates Sox9 in CNCC-derived Meckel's cartilage (MC), but not in limb cartilages. The MC-specific regulatory function of the PRS region cannot be attributed to the CNCC enhancers that have been inactivated in cartilages, but correlates with its MC-specific interactions with the Sox9 gene. By integrating the enhancer signatures and chromatin topology, we uncovered ~20,000 enhancers that function differentially between MC and limb cartilages and demonstrated their association with human diseases. Our findings highlight the importance of lineage-dependent chromatin topology in instructing enhancer usage and provide critical insights for interpreting the genetic basis of craniofacial pathologies.

ORGANISM(S): Mus musculus

PROVIDER: GSE185255 | GEO | 2023/01/04

REPOSITORIES: GEO

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Loss of extreme long-range enhancers in human neural crest drives a craniofacial disorder

Project description:Non-coding mutations at the far end of a large gene desert surrounding the SOX9 gene result in a human craniofacial disorder called Pierre Robin sequence (PRS). In this study we utilise epigenomic profiling of histone modifications and coactivator binding using ChIP-seq and chromatin accessibility using ATAC-seq to map cis-regulatory enhancer elements within the PRS locus during differentiation of human embryonic stem cells to cranial neural crest and chondrocytes. Strikingly, these enhancers are located up to 1.45 Mb away from the SOX9 gene promoter. We further perform RNA-sequencing to determine gene expression changes during the differentiation and identify potential transcription factors that regulate enhancer activity during CNCC development, including TWIST1. We utilise Capture-C from the SOX9 promoter to profile long-range interactions with the distal PRS-associated enhancer elements, and we confirm these interactions using reciprocal Capture-C from the identified candidate enhancer elements. Finally, we phase the H9 human embryonic stem cell line using 10X genomics linked-read sequencing in order link genetically edited alleles to gene expresssion changes in cis. Overall, we characterize the longest-range human enhancers involved in congenital malformations, directly demonstrate that PRS is an enhanceropathy, and identify one factor that may contribute to enhancer function in a developmentally-regulated manner.

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Foxc1 establishes enhancer accessibility for craniofacial cartilage differentiation

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2020-12-31 | GSE157575 | GEO

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ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial to mesenchymal transition in cranial neural crest lineage commitment.

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2024-07-23 | GSE261846 | GEO

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