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Series GSE230233 Query DataSets for GSE230233
Status Public on May 11, 2023
Title Pre-Hypertrophic Chondrogenic Enhancer Landscape of Limb and Axial Skeleton Development [ATAC-seq]
Organism Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary The precisely orchestrated differentiation of chondrocytes during skeleton development is a critical determinant of human height and body shape. Disruptions of this process can cause severe skeletal abnormalities. The ultimate size and shape of each of over 200 bones depends on the intricate spatiotemporal regulation of chondrogenic and chondrocyte differentiation genes, but the genomic architecture coordinating these events remains poorly defined. Here we provide a comprehensive map of transcriptional enhancers specifically active in chondrocytes and show that they provide a mechanistic framework through which noncoding genetic variants can influence human stature. We isolated limb and trunk fetal chondrocytes from mice with a Col2a1 fluorescent regulatory sensor and used RNA-seq to identify 780 genes that are specifically expressed during chondrogenesis. To create cell type-specific enhancer maps, we performed ATAC-seq to map open chromatin regions and ChIP-seq for H3K27ac, an enhancer-associated histone modification, and identified 2'704 putative chondrogenic enhancer regions. Most of these enhancers (74%) showed pan-chondrogenic activity, with smaller populations being restricted to limb (18%) or trunk (8%) chondrocytes only. We found that chondrogenic enhancers are enriched for the binding of several chondrogenic transcription factors including SOX9. Moreover, we find that genetic variation overlapping chondrogenic enhancers explains a higher fraction of the heritability of human adult height than the one overlapping non-chondrogenic enhancers. Finally, targeted deletions of identified enhancers at the Fgfr3, Col2a1, Hhip and, Nkx3-2 loci each exhibited a significant reduction of cognate gene expression, therefore demonstrating their functional importance. This data provides a comprehensive mapping of the chondrogenic enhancer repertoire, paving the way to interpreting the role of non-coding sequence polymorphisms in phenotypic variation and bone diseases.
Overall design We devised a Col2a1 fluroescent reporter approach to sort chondrocytes from embryonic trunk and limbs. We validate the specfici of the reproter using scRNAseq. We then analyse Col2a1-GFP positive and negative cells to profile their transcriptome, open chromatin and H3K27ac coverage to define enahncers and asssooicated genes.
Contributor(s) Andrey G, Darbellay F
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Submission date Apr 21, 2023
Last update date Feb 29, 2024
Contact name Guillaume Andrey
Phone +41223795703
Organization name University of Geneva
Department Department of Genetic Medicine and Development
Street address Rue Michel-Servet 1
City Geneva
ZIP/Postal code 1211
Country Switzerland
Platforms (1)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (8)
GSM7207917 ATACseq-L-E145-Col2a1GFP-GFPp-R1
GSM7207918 ATACseq-L-E145-Col2a1GFP-GFPp-R2
GSM7207919 ATACseq-L-E145-Col2a1GFP-GFPn-R1
This SubSeries is part of SuperSeries:
GSE230235 Pre-Hypertrophic Chondrogenic Enhancer Landscape of Limb and Axial Skeleton Development
BioProject PRJNA958101

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource 455.5 Mb (ftp)(http) BW 527.7 Mb (ftp)(http) BW 826.5 Mb (ftp)(http) BW 494.4 Mb (ftp)(http) BW
GSE230233_RAW.tar 2.1 Gb (http)(custom) TAR (of BW)
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Raw data are available in SRA
Processed data provided as supplementary file
Processed data are available on Series record

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