BCOR regulates mesenchymal stem cell function by epigenetic mechanisms

Abstract

BCOR (BCL6 co-repressor) represses gene transcription by interacting with BCL-6 1, 2. BCOR mutation is responsible for oculo-facio-cardio-dental (OFCD) syndrome, characterized by canine teeth with extremely long roots, congenital cataracts, craniofacial defects and congenital heart disease3–5. Here we show that BCOR mutation increased osteo/dentinogenic potentials of mesenchymal stem cells (MSCs) isolated from an OFCD patient, providing a molecular explanation for abnormal root growth. AP-2α was identified as a repressive target of BCOR, and BCOR mutation resulted in abnormal activation of AP-2α. Gain- and loss-of-function assays suggested that AP-2α was a key factor that mediated increased osteo/dentinogenic capacity of MSCs. Moreover, we found that BCOR maintained tissue homeostasis and gene silencing by epigenetic mechanisms. BCOR mutation increased histone H3K4/36 methylation in MSCs, thereby reactivating transcription of silenced target genes. In summary, by studying a rare human genetic disease, we unravel an epigenetic mechanism for control of human adult stem cell function.

Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved Therapeutic Potential

“…S5b). Although the question of how the epigenetic state of a cell influences fate determination has been previously addressed on ESCs, recent investigations focused on the role of epigenetic regulation in lineage-specific differentiation of MSCs have shown that unique patterns of DNA methylation and histone modifications play an important role in the induction of MSC differentiation toward specific lineages [47,48]. Particularly, it has been demonstrated that the modifiers of histone methylation can efficiently promote the generation of neural cells from MSCs [49,50].…”

Identification of One <em>BOCR</em> Mutation and Five <em>NF1</em> Mutations in Male Patients with Neurofibromatosis Type 1 and Congenital Pseudarthrosis of the Tibia

“…This repression may be mediated at least partially by class I and II histone deacetylases [20]. Furthermore, BCL-6 corepressor, involved in repression of TFAP2A, acts as a negative regulator of osteo-dentinogenic capacity in adult stem cells [21]. FBXL11 histone demethylase function was activated by associating with BCL-6 corepressor, and FBXL11 regulated osteo-dentinogenic differentiation in MSCs [22].…”

Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

“…However, KDM2B was shown to function as an oncogene by negatively regulating the expression of p15 ink4b tumorsuppressor gene via H3K36 demethylation in mouse embryonic fibroblasts and Hoxa9/Meis1-induced leukemia cells (12,13). In contrast, BCOR was shown to act as a growth suppressor in adult mesenchymal stem cells (MSC) isolated from a patient with oculofaciocardiodental (OFCD) syndrome because restoration of wildtype BCOR inhibited cell proliferation (14). Although a BCOR mutation significantly increased H3K36me2 methylation in the MSCs isolated from the patient with OFCD syndrome (MSC-O), gene expression profiling could not detect any differences between gene expression at the Ink4a-arf-ink4b locus in the MSC-O cells and that in wild-type MSCs (14).…”

“…In addition, BCOR regulates adult MSC functions through an epigenetic mechanism (14). The transcription factor AP-2a is developmentally important for the regulation of cell growth, programmed cell death, and differentiation.…”

“…The transcription factor AP-2a is developmentally important for the regulation of cell growth, programmed cell death, and differentiation. In the MSC-O cells, AP-2a was significantly overexpressed consequent to disengagement of BCOR complex repression on the AP-2a promoter (14). Moreover, BCOR mutations led to increased histone H3K36 methylation in the AP-2a promoter and decreased histone H2A ubiquitylation (14).…”