Integration of 3D Genome Topology and Local Chromatin Features Uncovers Enhancers Underlying Craniofacial-specific Cartilage Defects

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2022 Nov 23

PMID 36417512

Authors

Qiming Chen

Jiewen Dai

Qian Bian

Affiliations

Soon will be listed here.

Abstract

Aberrations in tissue-specific enhancers underlie many developmental defects. Disrupting a noncoding region distal from the human 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 that the PRS region also strongly regulates in CNCC-derived Meckel's cartilage (MC), but not in limb cartilages, even after decommissioning of CNCC enhancers. Such an MC-specific regulatory effect correlates with the MC-specific chromatin contacts between the PRS region and , highlighting the importance of lineage-dependent chromatin topology in instructing enhancer usage. By integrating the enhancer signatures and chromatin topology, we uncovered >10,000 enhancers that function differentially between MC and limb cartilages and demonstrated their association with human diseases. Our findings provide critical insights for understanding the choreography of gene regulation during development and interpreting the genetic basis of craniofacial pathologies.

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