A multiple super-enhancer region establishes inter-TAD interactions and controls Hoxa function in cranial neural...

Area of Science:

• Genomics
• Developmental Biology
• Molecular Biology

Background:

• Enhancer-promoter interactions are typically confined within topologically associating domains (TADs).
• Super-enhancers (SEs) are clusters of enhancers regulating high gene expression.
• The role of SEs in craniofacial development remains largely unexplored.

Purpose of the Study:

• To identify genome-wide super-enhancers (SEs) in mouse cranial neural crest cells (CNCCs).
• To investigate the topological regulatory impact of SEs on craniofacial development, specifically focusing on Hoxa genes.

Main Methods:

• Genome-wide identification of putative SEs in mouse CNCCs.
• Analysis of enhancer-promoter interactions and TAD insulation.
• Gene deletion studies (HIRE1, HIRE2) in Hoxa2 haploinsufficient models.

Main Results:

• Identified 2232 SEs in CNCCs, with 147 targeting genes crucial for facial development.
• Discovered a SE region (HIRE1/HIRE2) in PA2 CNCCs that interacts with Hoxa2, essential for ear development.
• HIRE2 deletion caused microtia; HIRE1 deletion mimicked Hoxa2 knockout, affecting PA3/PA4 CNCCs and Hoxa gene expression.

Conclusions:

• SEs can transcend TAD insulation to regulate gene expression in a cell-type-specific manner.
• SEs play a critical role in the collinear expression of anterior Hoxa genes during craniofacial development.
• This study reveals novel insights into SE-mediated regulation of craniofacial morphogenesis.