Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development

Article Article scientifique Article Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development eng 2024-06-06 2024-06-06 author Darbellay Fabrice 0000-0001-6942-3325 643868 Département de médecine génétique et développement (GEDEV) author Ramisch Anna 0000-0002-0641-4330 921603 Département de neurosciences fondamentales (NEUFO) author Lopez-Delisle Lucille 0000-0002-1964-4960 author Kosicki Michael author Rauseo Antonella 843600 Département de médecine génétique et développement (GEDEV) author Jouini Zahra 0009-0004-8188-7789 875092 Département de biologie moléculaire et cellulaire (MOCEL) author Visel Axel 0000-0002-4130-7784 author Andrey Guillaume 0000-0002-0911-4907 555493 Département de médecine génétique et développement (GEDEV) 4820 10.1038/s41467-024-49203-2 38844479 2041-1723 PMC11156918 https://www.nature.com/articles/s41467-024-49203-2 Chondrocyte differentiation controls skeleton development and stature. Here we provide a comprehensive map of chondrocyte-specific enhancers and show that they provide a mechanistic framework through which non-coding genetic variants can influence skeletal development and human stature. Working with fetal chondrocytes isolated from mice bearing a Col2a1 fluorescent regulatory sensor, we identify 780 genes and 2'704 putative enhancers specifically active in chondrocytes using a combination of RNA-seq, ATAC-seq and H3K27ac ChIP-seq. Most of these enhancers (74%) show pan -chondrogenic activity, with smaller populations being restricted to limb (18%) or trunk (8%) chondrocytes only. Notably, genetic variations overlapping these enhancers better explain height differences than those overlapping non-chondrogenic enhancers. Finally, targeted deletions of identified enhancers at the Fgfr3 , Col2a1 , Hhip and, Nkx3-2 loci confirm their role in regulating cognate genes. This enhancer map provides a framework for understanding how genes and non-coding variations influence bone development and diseases. Animals Bone Development / genetics Cell Differentiation / genetics Chondrocytes / cytology Chondrocytes / metabolism Chondrogenesis / genetics Collagen Type II / genetics Collagen Type II / metabolism Enhancer Elements, Genetic / genetics Extremities / embryology Female Gene Expression Regulation, Developmental Humans Male Mice Receptor, Fibroblast Growth Factor, Type 3 / genetics Receptor, Fibroblast Growth Factor, Type 3 / metabolism Transcription Factors / genetics Transcription Factors / metabolism Dewey 616.8 Dewey 590 Dewey 576.5 Swiss National Science Foundation Regulatory functions and mechanisms of dynamic chromatin interactions in vivo 176802 CH Careers Swiss National Science Foundation Regulatory functions and mechanisms of dynamic chromatin interactions in vivo 210996 CH Careers Swiss National Science Foundation Deciphering the regulatory landscape of Msx1 at single-cell resolution 194334 CH Careers 135 Département de médecine génétique et développement 21D 23 Institut de génétique et de génomique 0DH 53 Département de neurosciences fondamentales 21A false 1268 Contrôle épigénétique du développement embryonnaire 999 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE230235 https://www.ncbi.nlm.nih.gov/sra/?term=DRX028798 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE164738 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14305872 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14305873 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14305249 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14305250 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14305866 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14305867 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14306149 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14306150 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14306037 https://www.ncbi.nlm.nih.gov/sra/?term=SRR14306038 https://zenodo.org/records/7837436 Nature communications 15 1 f1368a2b-cb8a-4f35-909f-c550ac88da2c Article (Published version) Public Article_scientifique_from_crossref.pdf 2809387 application/pdf CC BY-4.0 ab79b9ea0a9c66bbed884ae9d1b958e3611c88f8ca5746cd8e26621cc0c3a57d 97c07949-c594-4a2e-b828-c4f2d91b8c8b Supplemental data Public 41467_2024_49203_MOESM1_ESM.pdf 7398716 application/pdf 5f4f2bd5723ce11064c4bd699898ca2f6bb26b4ec2be536970718d6c6317d2ef 9d490cf7-5dd3-44dd-b8cf-806396142a9d Supplemental data Public 41467_2024_49203_MOESM2_ESM.pdf 573043 application/pdf b14fd0169e983c12620a185756919dd2a5c4929f803ed7cfcfc662ed08cee6de e1ed0d9b-3acb-47a5-b926-08978999249e Supplemental data Public 41467_2024_49203_MOESM3_ESM.pdf 72364 application/pdf 6607ee31b28a6cab1fe99f51a45f33f5fd56823630d346dce403be5810fde32b 8e0ce12b-d0ba-4610-9b22-93e6a369bd1b Supplemental data Public 41467_2024_49203_MOESM4_ESM.xlsx 26695396 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 543ea88af97029f778c43fa7af471ff57b36620c1e2656c09335383c9088a9f0 acf74a12-b8f8-450b-a1be-44789f574994 Supplemental data Public 41467_2024_49203_MOESM5_ESM.mp4 35677819 video/mp4 248c280efaf845fd9d274dfdfb464471ef0d0e022f000aa3714c83b886dcb74b 3ab5df43-9865-4e58-a9a2-fcc75c4f076f Supplemental data Public 41467_2024_49203_MOESM6_ESM.pdf 186373 application/pdf 1dd9d8b98128e62f8f736b0a0919d3c87c852296c30071c62f81d7aa8fcc11f9 openAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement Centres et instituts / Institut de génétique et de génomique Faculté de médecine / Section de médecine fondamentale / Département de neurosciences fondamentales

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Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development	Nature communications			2024	86	43

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Ramisch, Anna