Kult, Shiri; Olender, Tsviya; Osterwalder, Marco; Markman, Svetalana; Leshkowitz, Dena; Krief, Sharon; Blecher-Gonen, Ronnie; Ben-Moshe, Shani; Farack, Lydia; Keren-Shaul, Hadas; Salame, Tomer-Meir; Capellini, Terence D; Itzkovitz, Shalev; Amit, Ido; Visel, Axel; Zelzer, Elazar (2021). Bi-fated tendon-to-bone attachment cells are regulated by shared enhancers and KLF transcription factors. eLife, 10 eLife Sciences Publications 10.7554/eLife.55361
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The mechanical challenge of attaching elastic tendons to stiff bones is solved by the formation of a unique transitional tissue. Here, we show that murine tendon-to-bone attachment cells are bi-fated, activating a mixture of chondrocyte and tenocyte transcriptomes, under regulation of shared regulatory elements and Krüppel-like factors (KLFs) transcription factors. High-throughput bulk and single-cell RNA sequencing of humeral attachment cells revealed expression of hundreds of chondrogenic and tenogenic genes, which was validated by in situ hybridization and single-molecule ISH. ATAC sequencing showed that attachment cells share accessible intergenic chromatin areas with either tenocytes or chondrocytes. Epigenomic analysis revealed enhancer signatures for most of these regions. Transgenic mouse enhancer reporter assays verified the shared activity of some of these enhancers. Finally, integrative chromatin and motif analyses and transcriptomic data implicated KLFs as regulators of attachment cells. Indeed, blocking expression of both Klf2 and Klf4 in developing limb mesenchyme impaired their differentiation.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) |
UniBE Contributor: |
Osterwalder, Marco |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2050-084X |
Publisher: |
eLife Sciences Publications |
Language: |
English |
Submitter: |
Marla Rittiner |
Date Deposited: |
24 Jan 2022 09:26 |
Last Modified: |
05 Dec 2022 16:00 |
Publisher DOI: |
10.7554/eLife.55361 |
PubMed ID: |
33448926 |
Uncontrolled Keywords: |
cartilage developmental biology enthesis mouse musculoskeletal system tendon |
BORIS DOI: |
10.48350/163436 |
URI: |
https://boris.unibe.ch/id/eprint/163436 |
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