HOXA cluster gene expression during osteoblast differentiation involves epigenetic control

Osteoporosis is a common skeletal disorder characterized by low bone mass leading to increased bone fragility and fracture susceptibility. In this study, we have identified pathways that stimulate differentiation of bone forming osteoblasts from human mesenchymal stromal cells (hMSCs). Gene expression profiling was performed in hMSCs differentiated toward osteoblasts (at 6 h). Significantly regulated genes were analyzed in silico, and the Connectivity Map (CMap) was used to identify candidate bone stimulatory compounds. The signature of parbendazole matches the expression changes observed for osteogenic hMSCs. Parbendazole stimulates osteoblast differentiation as indicated by increased alkaline phosphatase activity, mineralization, and up-regulation of bone marker genes (alkaline phosphatase/ALPL, osteopontin/SPP1, and bone sialoprotein II/IBSP) in a subset of the hMSC population resistant to the apoptotic effects of parbendazole. These osteogenic effects are independent of glucocorticoids because parbendazole does not up-regulate glucocorticoid receptor (GR) target genes and is not inhibited by the GR antagonist mifepristone. Parbendazole causes profound cytoskeletal changes including degradation of microtubules and increased focal adhesions. Stabilization of microtubules by pretreatment with Taxol inhibits osteoblast differentiation. Parbendazole up-regulates bone morphogenetic protein 2 (BMP-2) gene expression and activity. Cotreatment with the BMP-2 antagonist DMH1 limits, but does not block, parbendazole-induced mineralization. Using the CMap we have identified a previously unidentified lineage-specific, bone anabolic compound, parbendazole, which induces osteogenic differentiation through a combination of cytoskeletal changes and increased BMP-2 activity.

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Age-dependent Wnt gene expression in bone and during the course of osteoblast differentiation

AGE ◽

10.1007/s11357-008-9069-9 ◽

2008 ◽

Vol 30 (4) ◽

pp. 273-282 ◽

Cited By ~ 46

Author(s):

Martina Rauner ◽

Wolfgang Sipos ◽

Peter Pietschmann

Keyword(s):

Gene Expression ◽

Osteoblast Differentiation ◽

Age Dependent

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How to cluster gene expression dynamics in response to environmental signals

Briefings in Bioinformatics ◽

10.1093/bib/bbr032 ◽

2011 ◽

Vol 13 (2) ◽

pp. 162-174 ◽

Cited By ~ 26

Author(s):

Y. Wang ◽

M. Xu ◽

Z. Wang ◽

M. Tao ◽

J. Zhu ◽

...

Keyword(s):

Gene Expression ◽

Environmental Signals ◽

Gene Expression Dynamics ◽

Cluster Gene

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Differences in Gene Expression between Wild Type and Hoxa1 Knockout Embryonic Stem Cells after Retinoic Acid Treatment or Leukemia Inhibitory Factor (LIF) Removal

Journal of Biological Chemistry ◽

10.1074/jbc.m414397200 ◽

2005 ◽

Vol 280 (16) ◽

pp. 16484-16498 ◽

Cited By ~ 59

Author(s):

Eduardo Martinez-Ceballos ◽

Pierre Chambon ◽

Lorraine J. Gudas

Keyword(s):

Gene Expression ◽

Cell Proliferation ◽

Retinoic Acid ◽

Leukemia Inhibitory Factor ◽

Target Genes ◽

Hox Genes ◽

Es Cells ◽

Embryonic Stem ◽

Inhibitory Factor ◽

Hoxa Cluster

Homeobox (Hox) genes encode a family of transcription factors that regulate embryonic patterning and organogenesis. In embryos, alterations of the normal pattern of Hox gene expression result in homeotic transformations and malformations. Disruption of theHoxa1gene, the most 3′ member of the Hoxa cluster and a retinoic acid (RA) direct target gene, results in abnormal ossification of the skull, hindbrain, and inner ear deficiencies, and neonatal death. We have generated Hoxa1-/-embryonic stem (ES) cells (named Hoxa1-15) from Hoxa1-/-mutant blastocysts to study the Hoxa1 signaling pathway. We have characterized in detail these Hoxa1-/-ES cells by performing microarray analyses, and by this technique we have identified a number of putative Hoxa-1 target genes, including genes involved in bone development (e.g. Col1a1,Postn/Osf2, and the bone sialoprotein gene orBSP), genes that are expressed in the developing brain (e.g. Nnat,Wnt3a,BDNF,RhoB, andGbx2), and genes involved in various cellular processes (e.g. M-RAS,Sox17,Cdkn2b,LamA1,Col4a1,Foxa2,Foxq1,Klf5, andIgf2). Cell proliferation assays and Northern blot analyses of a number of ES cell markers (e.g. Rex1,Oct3/4,Fgf4, andBmp4) suggest that the Hoxa1 protein plays a role in the inhibition of cell proliferation by RA in ES cells. Additionally, Hoxa1-/-ES cells express high levels of various endodermal markers, includingGata4andDab2, and express much lessFgf5after leukemia inhibitory factor (LIF) withdrawal. Finally, we propose a model in which the Hoxa1 protein mediates repression of endodermal differentiation while promoting expression of ectodermal and mesodermal characteristics.

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Epigenetic control of BDNF gene expression and neural plasticity

Neuroscience Research ◽

10.1016/j.neures.2009.09.1592 ◽

2009 ◽

Vol 65 ◽

pp. S19

Author(s):

Masaaki Tsuda

Keyword(s):

Gene Expression ◽

Neural Plasticity ◽

Bdnf Gene ◽

Epigenetic Control

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Gene expression profiling of bone marrow mesenchymal stem cells from Osteogenesis Imperfecta patients during osteoblast differentiation

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2017.04.003 ◽

2017 ◽

Vol 60 (6) ◽

pp. 326-334 ◽

Cited By ~ 5

Author(s):

Carla Martins Kaneto ◽

Patrícia S. Pereira Lima ◽

Karen Lima Prata ◽

Jane Lima dos Santos ◽

João Monteiro de Pina Neto ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Osteogenesis Imperfecta ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Osteoblast Differentiation ◽

Marrow Mesenchymal Stem Cells

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miR-539 mediates osteoblast mineralization by regulating Distal-less genes 2 in MC3T3-E1 cell line

Open Life Sciences ◽

10.1515/biol-2017-0034 ◽

2017 ◽

Vol 12 (1) ◽

pp. 294-299 ◽

Cited By ~ 1

Author(s):

Jianguo Han ◽

Li Su ◽

Chunyang Zhang ◽

Rongcai Jiang

Keyword(s):

Gene Expression ◽

Alkaline Phosphatase ◽

Cell Line ◽

Osteoblast Differentiation ◽

Marker Gene ◽

Inhibitory Effect ◽

Negative Regulator ◽

Expression Level ◽

Matrix Mineralization ◽

Marker Gene Expression

AbstractmicroRNAs (miRNAs) play an important role in osteoblast differentiation. However, the mechanisms of miRNAs regulating osteoblast mineralization still needs to be further cleared. Distal-less genes 2 (Dlx2) plays an important role in osteoblast differentiation. We have found that miR-539 was significantly downregulated and Dlx2 was found to be inversely correlated with miR-539 in MC3T3-E1 cell line during osteoblast mineralization. The overexpression of miR-539 significantly decreased the expression level of Dlx2 and suppressed the osteogenic marker gene expression level, alkaline phosphatase activity and matrix mineralization. Our study showed that miR-539 was a negative regulator in osteoblast mineralization and that the targeting of Dlx2 gene partly contributes to this inhibitory effect exerted by miR-539.

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The discovery and importance of genomic imprinting

eLife ◽

10.7554/elife.42368 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 13

Author(s):

Anne C Ferguson-Smith ◽

Deborah Bourchis

Keyword(s):

Gene Expression ◽

Genomic Imprinting ◽

Genetic Disorders ◽

Epigenetic Inheritance ◽

Specific Gene ◽

Specific Gene Expression ◽

Epigenetic Control ◽

International Award ◽

Parent Of Origin ◽

Shed Light

The discovery of genomic imprinting by Davor Solter, Azim Surani and co-workers in the mid-1980s has provided a foundation for the study of epigenetic inheritance and the epigenetic control of gene activity and repression, especially during development. It also has shed light on a range of diseases, including both rare genetic disorders and common diseases. This article is being published to celebrate Solter and Surani receiving a 2018 Canada Gairdner International Award "for the discovery of mammalian genomic imprinting that causes parent-of-origin specific gene expression and its consequences for development and disease".

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