BCOR regulates mesenchymal stem cell function by epigenetic mechanisms.
The BCL-6 co-repressor (BCOR) represses gene transcription by interacting with BCL-6 (Refs 1, 2). BCOR mutation is responsible for oculo-facio-cardio-dental (OFCD) syndrome, which is characterized by canine teeth with extremely long roots, congenital cataracts, craniofacial defects and congenital heart disease. Here we show that BCOR mutation increased the osteo-dentinogenic potential of mesenchymal stem cells (MSCs) isolated from a patient with OFCD, providing a molecular explanation for abnormal root growth. AP-2alpha was identified as a repressive target of BCOR, and BCOR mutation resulted in abnormal activation of AP-2alpha. Gain- and loss-of-function assays suggest that AP-2alpha is a key factor that mediates the increased osteo-dentinogenic capacity of MSCs. Moreover, we found that BCOR maintained tissue homeostasis and gene silencing through epigenetic mechanisms. BCOR mutation increased histone H3K4 and H3K36 methylation in MSCs, thereby reactivating transcription of silenced target genes. By studying a rare human genetic disease, we have unravelled an epigenetic mechanism for control of human adult stem cell function.
Fan
Zhipeng
Z
Lab of Molecular Signaling, Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095, USA.
Yamaza
Takayoshi
T
Lee
Janice S
JS
Yu
Jinhua
J
Wang
Songlin
S
Fan
Guoping
G
Shi
Songtao
S
Wang
Cun-Yu
CY
D000015:Abnormalities, Multiple / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D017690:Cell Transplantation / Q000379:methods; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D005124:Eye Abnormalities; D005145:Face / Q000002:abnormalities; D005260:Female; D020869:Gene Expression Profiling; D006344:Heart Septal Defects, Atrial / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D008745:Methylation; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome; D014071:Tooth Abnormalities; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
C411984:BCOR protein, human; D006657:Histones; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C506895:SPP1 protein, human; D050656:Transcription Factor AP-2; D053495:Osteopontin