The Transcription Factor-microRNA Regulatory Network during hESC-chondrogenesis.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
16 03 2020
16 03 2020
Historique:
received:
08
08
2019
accepted:
19
02
2020
entrez:
18
3
2020
pubmed:
18
3
2020
medline:
15
12
2020
Statut:
epublish
Résumé
Human embryonic stem cells (ESCs) offer a promising therapeutic approach for osteoarthritis (OA). The unlimited source of cells capable of differentiating to chondrocytes has potential for repairing damaged cartilage or to generate disease models via gene editing. However their use is limited by the efficiency of chondrogenic differentiation. An improved understanding of the transcriptional and post-transcriptional regulation of chondrogenesis will enable us to improve hESC chondrogenic differentiation protocols. Small RNA-seq and whole transcriptome sequencing was performed on distinct stages of hESC-directed chondrogenesis. This revealed significant changes in the expression of several microRNAs including upregulation of known cartilage associated microRNAs and those transcribed from the Hox complexes, and the downregulation of pluripotency associated microRNAs. Integration of miRomes and transcriptomes generated during hESC-directed chondrogenesis identified key functionally related clusters of co-expressed microRNAs and protein coding genes, associated with pluripotency, primitive streak, limb development and extracellular matrix. Analysis identified regulators of hESC-directed chondrogenesis such as miR-29c-3p with 10 of its established targets identified as co-regulated 'ECM organisation' genes and miR-22-3p which is highly co-expressed with ECM genes and may regulate these genes indirectly by targeting the chondrogenic regulators SP1 and HDAC4. We identified several upregulated transcription factors including HOXA9/A10/D13 involved in limb patterning and RELA, JUN and NFAT5, which have targets enriched with ECM associated genes. We have developed an unbiased approach for integrating transcriptome and miRome using protein-protein interactions, transcription factor regulation and miRNA target interactions and identified key regulatory networks prominent in hESC chondrogenesis.
Identifiants
pubmed: 32179818
doi: 10.1038/s41598-020-61734-4
pii: 10.1038/s41598-020-61734-4
pmc: PMC7075910
doi:
Substances chimiques
MicroRNAs
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4744Subventions
Organisme : Medical Research Council
ID : MR/K017047/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : 1574988
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K026666/1
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : 18872
Pays : United Kingdom
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