Lineage-specific differences and regulatory networks governing human chondrocyte development
To address large gaps in our understanding of the molecular regulation of articular and growth plate cartilage development in humans, we used our directed differentiation approach to generate these distinct cartilage tissues from human embryonic stem cells. The resulting transcriptomic profiles of hESC-derived articular and growth plate chondrocytes were similar to fetal epiphyseal and growth plate chondrocytes, with respect to genes both known and previously unknown to cartilage biology. With the goal to characterize the regulatory landscapes accompanying these respective transcriptomes, we mapped chromatin accessibility in hESC-derived chondrocyte lineages, and mouse embryonic chondrocytes, using ATAC-sequencing. Integration of the expression dataset with the differentially accessible genomic regions revealed lineage-specific gene regulatory networks. We validated functional interactions of two transcription factors (RUNX2 in growth plate chondrocytes and RELA in articular chondrocytes) with their predicted genomic targets. The maps we provide thus represent a framework for probing regulatory interactions governing chondrocyte differentiation. This work constitutes a substantial step towards comprehensive and comparative molecular characterizations of distinct chondrogenic lineages, and sheds new light on human cartilage development and biology.
The accession number for the raw ATAC-seq and RNA-seq datasets reported in this paper will be publicly available upon acceptance on GEO under accession GSE195688.
Lineage-Specific Differences and Inference of Regulatory Networks Governing Human Chondrocyte DevelopmentNCBI Gene Expression Omnibus, GSE195688.
Regulatory constraint and selection during human knee evolution drive modern osteoarthritis riskNCBI Gene Expression Omnibus, GSE122877.
Article and author information
- April M Craft
- Terence D Capellini
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal work was performed according to approved institutional animal care and use committee protocols at Harvard University (IACUC 13-04-161).
Human subjects: Human fetal donor samples were collected from the first trimester termination via the University of Washington (UW) Birth Defects Research Laboratory (BRDL) in full compliance with the ethical guidelines of the NIH and with the approval of UW Review Boards for the collection and distribution of human tissue for research, and Harvard University and Boston Children's Hospital for the receipt and use of such materials, and Harvard University and Boston Children's Hospital for the receipt and use of such materials (Capellini: IRB16-1504; Craft: IRB-P00017303). This is not deemed human subjects research.All reported research involving human embryonic stem cells was approved by IRB (IRB-P00017303) and ESCRO (ESCRO-2015.4.24) regulatory bodies at Boston Children's Hospital.
- Di Chen, Chinese Academy of Sciences, China
- Received: May 3, 2022
- Preprint posted: May 25, 2022 (view preprint)
- Accepted: March 14, 2023
- Accepted Manuscript published: March 15, 2023 (version 1)
© 2023, Richard et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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