Epigenetic regulation of early osteogenesis and mineralized tissue formation by a HOXA10-PBX1-associated complex
Authors
Gordon, Jonathan A. R.Hassan, Mohammad Q.
Koss, Matthew
Montecino, Martin A.
Selleri, Licia
Van Wijnen, Andre J.
Stein, Janet L.
Stein, Gary S.
Lian, Jane B.
UMass Chan Affiliations
Department of Cell BiologyDocument Type
Journal ArticlePublication Date
2011-05-19Keywords
AnimalsBone Marrow Cells
Calcification, Physiologic
Cell Differentiation
*Epigenesis, Genetic
*Gene Expression Regulation, Developmental
HEK293 Cells
Homeodomain Proteins
Humans
Mice
Multiprotein Complexes
Osteoblasts
Osteogenesis
Promoter Regions, Genetic
RNA, Small Interfering
Stromal Cells
Transcription Factors
Cell Biology
Metadata
Show full item recordAbstract
Homeodomain-containing (HOX) factors such as the abdominal class homeodomain protein HOXA10 and the TALE-family protein PBX1 form coregulatory complexes and are potent transcriptional and epigenetic regulators of tissue morphogenesis. We have identified that HOXA10 and PBX1 are expressed in osteoprogenitors; however, their role in osteogenesis has not been established. To determine the mechanism of HOXA10-PBX-mediated regulation of osteoblast commitment and the related gene expression, PBX1 or HOX10 were depleted (shRNA or genetic deletion, respectively) or exogenously expressed in C3H10T1/2, bone marrow stromal progenitors, and MC3T3-E1 (preosteoblast) cells. Overexpression of HOXA10 increased the expression of osteoblast-related genes, osteoblast differentiation and mineralization; expression of PBX1 impaired osteogenic commitment of pluripotent cells and the differentiation of osteoblasts. In contrast, the targeted depletion of PBX1 by shRNA increased the expression of bone marker genes (osterix, alkaline phosphatase, BSP, and osteocalcin). Chromatin-associated PBX1 and HOXA10 were present at osteoblast-related gene promoters preceding gene expression, but PBX1 was absent from promoters during the transcription of bone-related genes, including osterix (Osx). Further, PBX1 complexes were associated with histone deacetylases normally linked with chromatin inactivation. Loss of PBX1 but not of HOXA10 from the Osx promoter was associated with increases in the recruitment of histone acetylases (p300), as well as decreased H3K9 methylation, reflecting transcriptional activation. We propose PBX1 plays a central role in attenuating the activity of HOXA10 as an activator of osteoblast-related genes and functions to establish the proper timing of gene expression during osteogenesis, resulting in proper matrix maturation and mineral deposition in differentiated osteoblasts.Source
Cells Tissues Organs. 2011;194(2-4):146-50. Epub 2011 May 19. Link to article on publisher's siteDOI
10.1159/000324790Permanent Link to this Item
http://hdl.handle.net/20.500.14038/49584PubMed ID
21597276Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1159/000324790