Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer
| Autor: | Raquel Rouco, Olimpia Bompadre, Antonella Rauseo, Olivier Fazio, Rodrigue Peraldi, Fabrizio Thorel, Guillaume Andrey |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Hindlimb / embryology
Limb Buds Science General Physics and Astronomy Development General Biochemistry Genetics and Molecular Biology Article Epigenesis Genetic 03 medical and health sciences Hindlimb / cytology Paired Box Transcription Factors / metabolism Mice 0302 clinical medicine ddc:590 Chromatin / chemistry Developmental biology Animals Paired Box Transcription Factors ddc:576.5 Enhancer Elements Genetic / genetics 030304 developmental biology Hindlimb / metabolism Sequence Deletion 0303 health sciences Multidisciplinary Models Genetic Paired Box Transcription Factors / genetics Gene Expression Regulation Developmental Limb Buds / embryology RNA sequencing Acetylation General Chemistry Limb Buds / cytology Limb Buds / metabolism Genetic models Embryo Mammalian Chromatin Gene regulation Hindlimb Chromatin / metabolism Enhancer Elements Genetic Connective Tissue Connective Tissue / growth & development Connective Tissue / metabolism 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-15 (2021) Nature communications, Vol. 12, No 1 (2021) P. 7235 |
| ISSN: | 2041-1723 |
| Popis: | 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. Developmental genes are frequently controlled by multiple enhancers sharing similar specificities, so deletions of such regulatory elements often fail to reveal their full function. Here the authors use the Pitx1 testbed locus to characterize the regulatory and cellular identity alterations following the deletion in vivo of one of its enhancers. |
| Databáze: | OpenAIRE |
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