Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer

Article Article scientifique Article Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer eng 2021-12-13 2021-12-13 author Rouco Raquel 0000-0002-0657-0704 927044 author Bompadre Olimpia 0000-0002-8334-6538 917778 author Rauseo Antonella 843600 author Fazio Olivier 132967 author Peraldi Rodrigue 816551 author Thorel Fabrizio 501462 author Andrey Guillaume 0000-0002-0911-4907 555493 7235 10.1038/s41467-021-27492-1 34903763 2041-1723 PMC8668926 Developmental genes are frequently controlled by multiple enhancers sharing similar specificities. As a result, deletions of such regulatory elements have often failed to reveal their full function. Here, we use the Pitx1 testbed locus to characterize in detail the regulatory and cellular identity alterations following the deletion of one of its enhancers (Pen). By combining single cell transcriptomics and an in-embryo cell tracing approach, we observe an increased fraction of Pitx1 non/low-expressing cells and a decreased fraction of Pitx1 high-expressing cells. We find that the over-representation of Pitx1 non/low-expressing cells originates from a failure of the Pitx1 locus to coordinate enhancer activities and 3D chromatin changes. This locus mis-activation induces a localized heterochrony and a concurrent loss of irregular connective tissue, eventually leading to a clubfoot phenotype. This data suggests that, in some cases, redundant enhancers may be used to locally enforce a robust activation of their host regulatory landscapes. Acetylation Animals Chromatin / chemistry Chromatin / metabolism Connective Tissue / growth & development Connective Tissue / metabolism Embryo, Mammalian Enhancer Elements, Genetic / genetics Epigenesis, Genetic Gene Expression Regulation, Developmental Hindlimb / cytology Hindlimb / embryology Hindlimb / metabolism Limb Buds / cytology Limb Buds / embryology Limb Buds / metabolism Mice Models, Genetic Paired Box Transcription Factors / genetics Paired Box Transcription Factors / metabolism Sequence Deletion Dewey 590 Dewey 576.5 Swiss National Science Foundation Regulatory functions and mechanisms of dynamic chromatin interactions in vivo PP00P3_176802 CH Careers 135 Département de médecine génétique et développement 21D 23 Institut de génétique et de génomique 0DH false 1268 Contrôle épigénétique du développement embryonnaire 999 Nature communications 12 1 ffa1857c-a4ad-4fdf-b8b4-8ce02c80516c Article (Published version) Public Article-scientifique-from-unpaywall.pdf 8852276 application/pdf CC BY-4.0 openAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Centres et instituts / Institut de génétique et de génomique

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Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer	Nature communications			2021	219	238

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Fazio, Olivier