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Series GSE144306 Query DataSets for GSE144306
Status Public on Jan 27, 2021
Title Bi-fated tendon-to-bone attachment cells are regulated by shared enhancers and KLF transcription factors
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
Summary "The connection between different tissues is vital for the development and function of all organs and systems. In the musculoskeletal system, the attachment of elastic tendons to stiff bones poses a mechanical challenge that is solved by the formation of a transitional tissue, which allows the transfer of muscle forces to the skeleton without tearing. Here, we show that tendon-to-bone attachment cells are bi-fated, activating a mixture of
chondrocyte and tenocyte transcriptomes, which is regulated by sharing regulatory elements with these cells and by Krüppel-like factors transcription factors (KLF).
To uncover the molecular identity of attachment cells, we first applied high-throughput bulk and single-cell RNA sequencing to murine humeral attachment cells. The results, which were validated by in situ and single-molecule in situ hybridization, reveal that together with the expression of unique sets of genes, the attachment cells express hundreds of chondrogenic and tenogenic genes. In search for the underlying mechanism, we performed ATAC sequencing and found that attachment cells share a significant fraction of accessible intergenic chromatin areas with either tenocytes or chondrocytes. Epigenomic analysis further revealed transcriptional enhancer signatures for the majority of these regions. We then examined a subset of these regions using transgenic mouse enhancer reporter assay. Results verified the shared activity of some of these enhancers, supporting the possibility that the transcriptome of attachment cells is regulated by enhancers with shared activities in tenocytes or chondrocytes. Finally, integrative chromatin and motif analyses, as well as the transcriptome data, indicated that KLFs are regulators of attachment cells. Indeed, blocking the expression of Klf2 and Klf4 in the developing limb mesenchyme led to abnormal differentiation of attachment cells, establishing these factors as key regulators of the fate of these cells. In summary, our findings show how the molecular identity of bi-fated attachment cells enables the formation of the unique transitional tissue that connects tendon to bone. More broadly, we show how mixing the transcriptomes of two cell types through shared enhancers and a dedicated set of transcription factors can lead to the formation of a new cell fate that connects them."

 
Overall design Comparative transcriptome analysis of tenocytes, attachment cells and chondrocytes populations, isolated by laser capture microdissection (LCM). ATACseq data were measured from E13.5 tenocytes, attachment cells and chondrocytes isolated by FACS sorting;attachment cells genetically co-labeled Sox9-CreERT2;Rosa26-tdTomato+;ScxGFP+, tenocytes genetically labeled by ScxGFP+, chondrocytes genetically labeled Col2-CreERT; Rosa26-tdTomato+;ScxGFP-.
 
Contributor(s) Kult S, Olender T, Osterwalder M, Markman S, Leshkowitz D, Krief S, Blecher-Gonen R, Ben-Moshe S, Farack L, Keren-Shaul H, Salame TM, Capellini TD, Itzkovitz S, Amit I, Visel A, Zelzer E
Citation(s) 33448926
Submission date Jan 27, 2020
Last update date Feb 02, 2021
Contact name Tsviya Olender
E-mail(s) tsviya.olender@weizmann.ac.il
Organization name The Weizmann Institute
Department Molecular Genetics
Street address 234 Herzl St.
City Rehovot
ZIP/Postal code 7610001
Country Israel
 
Platforms (2)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (20)
GSM4285535 remote tenocyte [A1]
GSM4285536 remote tenocyte [A2]
GSM4285537 adjacent tenocyte [B1]
Relations
BioProject PRJNA603341
SRA SRP245396

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE144306_ATACseq_peaks_readCount.txt.gz 1.6 Mb (ftp)(http) TXT
GSE144306_MARseq_day14.5_crudeReadCount.txt.gz 12.9 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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