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

Sandra Kessler, Maryline Minoux, Onkar Joshi, Yousra Zouari, Sebastien Ducret, Fiona Ross, Nathalie Vilain, Adwait Salvi, Joachim Wolff, Hubertus Kohler, Michael B. Stadler and Filippo M. Rijli ()
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Sandra Kessler: Friedrich Miescher Institute for Biomedical Research
Maryline Minoux: Friedrich Miescher Institute for Biomedical Research
Onkar Joshi: Friedrich Miescher Institute for Biomedical Research
Yousra Zouari: Friedrich Miescher Institute for Biomedical Research
Sebastien Ducret: Friedrich Miescher Institute for Biomedical Research
Fiona Ross: Friedrich Miescher Institute for Biomedical Research
Nathalie Vilain: Friedrich Miescher Institute for Biomedical Research
Adwait Salvi: Friedrich Miescher Institute for Biomedical Research
Joachim Wolff: Friedrich Miescher Institute for Biomedical Research
Hubertus Kohler: Friedrich Miescher Institute for Biomedical Research
Michael B. Stadler: Friedrich Miescher Institute for Biomedical Research
Filippo M. Rijli: Friedrich Miescher Institute for Biomedical Research

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: Abstract Enhancer-promoter interactions preferentially occur within boundary-insulated topologically associating domains (TADs), limiting inter-TAD interactions. Enhancer clusters in linear proximity, termed super-enhancers (SEs), ensure high target gene expression levels. Little is known about SE topological regulatory impact during craniofacial development. Here, we identify 2232 genome-wide putative SEs in mouse cranial neural crest cells (CNCCs), 147 of which target genes establishing CNCC positional identity during face formation. In second pharyngeal arch (PA2) CNCCs, a multiple SE-containing region, partitioned into Hoxa Inter-TAD Regulatory Element 1 and 2 (HIRE1 and HIRE2), establishes long-range inter-TAD interactions selectively with Hoxa2, that is required for external and middle ear structures. HIRE2 deletion in a Hoxa2 haploinsufficient background results in microtia. HIRE1 deletion phenocopies the full homeotic Hoxa2 knockout phenotype and induces PA3 and PA4 CNCC abnormalities correlating with Hoxa2 and Hoxa3 transcriptional downregulation. Thus, SEs can overcome TAD insulation and regulate anterior Hoxa gene collinear expression in a CNCC subpopulation-specific manner during craniofacial development.

Date: 2023
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DOI: 10.1038/s41467-023-38953-0

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