PMID- 36383652
OWN - NLM
STAT- MEDLINE
DCOM- 20221118
LR  - 20230720
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 8
IP  - 46
DP  - 2022 Nov 18
TI  - CTR9 drives osteochondral lineage differentiation of human mesenchymal stem cells 
      via epigenetic regulation of BMP-2 signaling.
PG  - eadc9222
LID - 10.1126/sciadv.adc9222 [doi]
LID - eadc9222
AB  - Cell fate determination of human mesenchymal stem/stromal cells (hMSCs) is 
      precisely regulated by lineage-specific transcription factors and epigenetic 
      enzymes. We found that CTR9, a key scaffold subunit of polymerase-associated 
      factor complex (PAFc), selectively regulates hMSC differentiation to osteoblasts 
      and chondrocytes, but not to adipocytes. An in vivo ectopic osteogenesis assay 
      confirmed the essentiality of CTR9 in hMSC-derived bone formation. CTR9 
      counteracts the activity of Enhancer Of Zeste 2 (EZH2), the epigenetic enzyme 
      that deposits H3K27me3, in hMSCs. Accordingly, CTR9 knockdown (KD) hMSCs gain 
      H3K27me3 mark, and the osteogenic differentiation defects of CTR9 KD hMSCs can be 
      partially rescued by treatment with EZH2 inhibitors. Transcriptome analyses 
      identified bone morphology protein-2 (BMP-2) as a downstream effector of CTR9. 
      BMP-2 secretion, membrane anchorage, and the BMP-SMAD pathway were impaired in 
      CTR9 KD MSCs, and the effects were rescued by BMP-2 supplementation. This study 
      uncovers an epigenetic mechanism engaging the CTR9-H3K27me3-BMP-2 axis to 
      regulate the osteochondral lineage differentiation of hMSCs.
FAU - Chan, Ngai Ting
AU  - Chan NT
AUID- ORCID: 0000-0002-6203-9109
AD  - McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, 
      University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI 53706, 
      USA.
FAU - Lee, Ming-Song
AU  - Lee MS
AUID- ORCID: 0000-0001-7660-1900
AD  - Department of Orthopedics and Rehabilitation, School of Medicine and Public 
      Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
FAU - Wang, Yidan
AU  - Wang Y
AUID- ORCID: 0000-0002-1417-8059
AD  - McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, 
      University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI 53706, 
      USA.
FAU - Galipeau, Jacques
AU  - Galipeau J
AUID- ORCID: 0000-0002-9374-1996
AD  - Department of Medicine, School of Medicine and Public Health, University of 
      Wisconsin-Madison, Madison, WI 53706, USA.
FAU - Li, Wan-Ju
AU  - Li WJ
AUID- ORCID: 0000-0002-6579-8063
AD  - Department of Orthopedics and Rehabilitation, School of Medicine and Public 
      Health, University of Wisconsin-Madison, Madison, WI 53706, USA.
FAU - Xu, Wei
AU  - Xu W
AUID- ORCID: 0000-0003-3808-0045
AD  - McArdle Laboratory for Cancer Research, Wisconsin Institute for Medical Research, 
      University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI 53706, 
      USA.
LA  - eng
GR  - R01 CA236356/CA/NCI NIH HHS/United States
GR  - R01 CA268183/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20221116
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
RN  - 0 (Histones)
RN  - 0 (CTR9 protein, human)
RN  - 0 (Phosphoproteins)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Humans
MH  - *Osteogenesis
MH  - *Mesenchymal Stem Cells/metabolism
MH  - Epigenesis, Genetic
MH  - Histones/metabolism
MH  - Cell Differentiation/genetics
MH  - Osteoblasts
MH  - Phosphoproteins/metabolism
MH  - Transcription Factors/metabolism
PMC - PMC9668309
EDAT- 2022/11/17 06:00
MHDA- 2022/11/19 06:00
PMCR- 2022/11/16
CRDT- 2022/11/16 14:05
PHST- 2022/11/16 14:05 [entrez]
PHST- 2022/11/17 06:00 [pubmed]
PHST- 2022/11/19 06:00 [medline]
PHST- 2022/11/16 00:00 [pmc-release]
AID - adc9222 [pii]
AID - 10.1126/sciadv.adc9222 [doi]
PST - ppublish
SO  - Sci Adv. 2022 Nov 18;8(46):eadc9222. doi: 10.1126/sciadv.adc9222. Epub 2022 Nov 
      16.