IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-49203-2.html
   My bibliography  Save this article

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

Author

Listed:
  • Fabrice Darbellay

    (University of Geneva
    University of Geneva
    Lawrence Berkeley Laboratory)

  • Anna Ramisch

    (University of Geneva)

  • Lucille Lopez-Delisle

    (Ecole Polytechnique Fédérale de Lausanne (EPFL))

  • Michael Kosicki

    (Lawrence Berkeley Laboratory)

  • Antonella Rauseo

    (University of Geneva
    University of Geneva)

  • Zahra Jouini

    (University of Geneva
    University of Geneva)

  • Axel Visel

    (Lawrence Berkeley Laboratory
    Lawrence Berkeley Laboratory
    University of California)

  • Guillaume Andrey

    (University of Geneva
    University of Geneva)

Abstract

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.

Suggested Citation

  • Fabrice Darbellay & Anna Ramisch & Lucille Lopez-Delisle & Michael Kosicki & Antonella Rauseo & Zahra Jouini & Axel Visel & Guillaume Andrey, 2024. "Pre-hypertrophic chondrogenic enhancer landscape of limb and axial skeleton development," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49203-2
    DOI: 10.1038/s41467-024-49203-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-49203-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-49203-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Wouter de Laat & Denis Duboule, 2013. "Topology of mammalian developmental enhancers and their regulatory landscapes," Nature, Nature, vol. 502(7472), pages 499-506, October.
    2. Alvaro Rada-Iglesias & Ruchi Bajpai & Tomek Swigut & Samantha A. Brugmann & Ryan A. Flynn & Joanna Wysocka, 2011. "A unique chromatin signature uncovers early developmental enhancers in humans," Nature, Nature, vol. 470(7333), pages 279-283, February.
    3. Raquel Rouco & Olimpia Bompadre & Antonella Rauseo & Olivier Fazio & Rodrigue Peraldi & Fabrizio Thorel & Guillaume Andrey, 2021. "Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    4. Shalu Jhanwar & Jonas Malkmus & Jens Stolte & Olga Romashkina & Aimée Zuniga & Rolf Zeller, 2021. "Conserved and species-specific chromatin remodeling and regulatory dynamics during mouse and chicken limb bud development," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    5. Loïc Yengo & Sailaja Vedantam & Eirini Marouli & Julia Sidorenko & Eric Bartell & Saori Sakaue & Marielisa Graff & Anders U. Eliasen & Yunxuan Jiang & Sridharan Raghavan & Jenkai Miao & Joshua D. Aria, 2022. "A saturated map of common genetic variants associated with human height," Nature, Nature, vol. 610(7933), pages 704-712, October.
    6. Michiko Yoshida & Kenji Hata & Rikako Takashima & Koichiro Ono & Eriko Nakamura & Yoshifumi Takahata & Tomohiko Murakami & Sachiko Iseki & Teruko Takano-Yamamoto & Riko Nishimura & Toshiyuki Yoneda, 2015. "The transcription factor Foxc1 is necessary for Ihh–Gli2-regulated endochondral ossification," Nature Communications, Nature, vol. 6(1), pages 1-15, May.
    7. Marco Osterwalder & Iros Barozzi & Virginie Tissières & Yoko Fukuda-Yuzawa & Brandon J. Mannion & Sarah Y. Afzal & Elizabeth A. Lee & Yiwen Zhu & Ingrid Plajzer-Frick & Catherine S. Pickle & Momoe Kat, 2018. "Enhancer redundancy provides phenotypic robustness in mammalian development," Nature, Nature, vol. 554(7691), pages 239-243, February.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Raquel Rouco & Olimpia Bompadre & Antonella Rauseo & Olivier Fazio & Rodrigue Peraldi & Fabrizio Thorel & Guillaume Andrey, 2021. "Cell-specific alterations in Pitx1 regulatory landscape activation caused by the loss of a single enhancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Christopher Chase Bolt & Lucille Lopez-Delisle & Aurélie Hintermann & Bénédicte Mascrez & Antonella Rauseo & Guillaume Andrey & Denis Duboule, 2022. "Context-dependent enhancer function revealed by targeted inter-TAD relocation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Andrea Wilderman & Eva D’haene & Machteld Baetens & Tara N. Yankee & Emma Wentworth Winchester & Nicole Glidden & Ellen Roets & Jo Dorpe & Sandra Janssens & Danny E. Miller & Miranda Galey & Kari M. B, 2024. "A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    4. Pau Farré & Eldon Emberly, 2018. "A maximum-entropy model for predicting chromatin contacts," PLOS Computational Biology, Public Library of Science, vol. 14(2), pages 1-16, February.
    5. Xiaofeng Zhu & Yihe Yang & Noah Lorincz-Comi & Gen Li & Amy R. Bentley & Paul S. de Vries & Michael Brown & Alanna C. Morrison & Charles N. Rotimi & W. James Gauderman & Dabeeru C. Rao & Hugues Aschar, 2024. "An approach to identify gene-environment interactions and reveal new biological insight in complex traits," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Jan-Renier Moonen & James Chappell & Minyi Shi & Tsutomu Shinohara & Dan Li & Maxwell R. Mumbach & Fan Zhang & Ramesh V. Nair & Joseph Nasser & Daniel H. Mai & Shalina Taylor & Lingli Wang & Ross J. M, 2022. "KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Victor Lopez Soriano & Alfredo Dueñas Rey & Rajarshi Mukherjee & Frauke Coppieters & Miriam Bauwens & Andy Willaert & Elfride De Baere, 2024. "Multi-omics analysis in human retina uncovers ultraconserved cis-regulatory elements at rare eye disease loci," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    8. Yanting Luo & Jianlin He & Xiguang Xu & Ming-an Sun & Xiaowei Wu & Xuemei Lu & Hehuang Xie, 2018. "Integrative single-cell omics analyses reveal epigenetic heterogeneity in mouse embryonic stem cells," PLOS Computational Biology, Public Library of Science, vol. 14(3), pages 1-21, March.
    9. Renata Bordeira-Carriço & Joana Teixeira & Marta Duque & Mafalda Galhardo & Diogo Ribeiro & Rafael D. Acemel & Panos. N. Firbas & Juan J. Tena & Ana Eufrásio & Joana Marques & Fábio J. Ferreira & Telm, 2022. "Multidimensional chromatin profiling of zebrafish pancreas to uncover and investigate disease-relevant enhancers," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Daniela Michelatti & Sven Beyes & Chiara Bernardis & Maria Luce Negri & Leonardo Morelli & Naiara Garcia Bediaga & Vittoria Poli & Luca Fagnocchi & Sara Lago & Sarah D’Annunzio & Nicole Cona & Ilaria , 2024. "Oncogenic enhancers prime quiescent metastatic cells to escape NK immune surveillance by eliciting transcriptional memory," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    11. Dongmei Wang & Haimin Li & Navdeep S. Chandel & Yali Dou & Rui Yi, 2023. "MOF-mediated histone H4 Lysine 16 acetylation governs mitochondrial and ciliary functions by controlling gene promoters," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    12. Ozvan Bocher & Cristen J. Willer & Eleftheria Zeggini, 2023. "Unravelling the genetic architecture of human complex traits through whole genome sequencing," Nature Communications, Nature, vol. 14(1), pages 1-4, December.
    13. François Serra & Andrea Nieto-Aliseda & Lucía Fanlo-Escudero & Llorenç Rovirosa & Mónica Cabrera-Pasadas & Aleksey Lazarenkov & Blanca Urmeneta & Alvaro Alcalde-Merino & Emanuele M. Nola & Andrei L. O, 2024. "p53 rapidly restructures 3D chromatin organization to trigger a transcriptional response," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    14. Liza Darrous & Gibran Hemani & George Davey Smith & Zoltán Kutalik, 2024. "PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    15. Michael S. Werner & Tobias Loschko & Thomas King & Shelley Reich & Tobias Theska & Mirita Franz-Wachtel & Boris Macek & Ralf J. Sommer, 2023. "Histone 4 lysine 5/12 acetylation enables developmental plasticity of Pristionchus mouth form," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    16. Xuemeng Zhou & Tsz Wing Sam & Ah Young Lee & Danny Leung, 2021. "Mouse strain-specific polymorphic provirus functions as cis-regulatory element leading to epigenomic and transcriptomic variations," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    17. Mattia Zaghi & Federica Banfi & Luca Massimino & Monica Volpin & Edoardo Bellini & Simone Brusco & Ivan Merelli & Cristiana Barone & Michela Bruni & Linda Bossini & Luigi Antonio Lamparelli & Laura Pi, 2023. "Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    18. Prachand Issarapu & Manisha Arumalla & Hannah R. Elliott & Suraj S. Nongmaithem & Alagu Sankareswaran & Modupeh Betts & Sara Sajjadi & Noah J. Kessler & Swati Bayyana & Sohail R. Mansuri & Maria Derak, 2023. "DNA methylation at the suppressor of cytokine signaling 3 (SOCS3) gene influences height in childhood," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    19. B. Edginton-White & A. Maytum & S. G. Kellaway & D. K. Goode & P. Keane & I. Pagnuco & S. A. Assi & L. Ames & M. Clarke & P. N. Cockerill & B. Göttgens & J. B. Cazier & C. Bonifer, 2023. "A genome-wide relay of signalling-responsive enhancers drives hematopoietic specification," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    20. Chaitali Chakraborty & Itzel Nissen & Craig A. Vincent & Anna-Carin Hägglund & Andreas Hörnblad & Silvia Remeseiro, 2023. "Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49203-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.