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Title: Global gene expression analysis identifies Mef2c as a potential player in Wnt16-mediated transcriptional regulation

Wnt16 is a major Wnt ligand involved in the regulation of postnatal bone homeostasis. Previous studies have shown that Wnt16 promotes bone formation and inhibits bone resorption, suggesting that this molecule could be targeted for therapeutic interventions to treat bone thinning disorders such as osteoporosis. However, the molecular mechanisms by which Wnt16 regulates bone metabolism is not yet fully understood. To better understand the molecular mechanisms by which Wnt16 promotes bone formation and to identify the target genes regulated by Wnt16 in osteoblasts, we treated calvarial osteoblasts purified from C57Bl/6 mice with recombinant Wnt16 and profiled the gene expression changes by RNA-seq at 24 h post-treatment. We also compared gene expression profiles of Wnt16-treated osteoblasts to canonical Wnt3a- and non-canonical Wnt5a-treated osteoblasts. This study identified 576 genes differentially expressed in Wnt16-treated osteoblasts compared to sham-treated controls; these included several members of Wnt pathway (Wnt2b, Wnt7b, Wnt11, Axin2, Sfrp2, Sfrp4, Fzd5 etc.) and TGF-β/BMP signaling pathway (Bmp7, Inhba, Inhbb, Tgfb2 etc.). Wnt16 also regulated a large number of genes with known bone phenotypes. We also found that about 37% (215/576) of the Wnt16 targets overlapped with Wnt3a targets and ~15% (86/576) overlapped with Wnt5a targets, suggesting that Wnt16 activates both canonicalmore » and non-canonical Wnt signaling targets in osteoblasts. Transcription factor binding motif enrichment analysis in the promoter regions of Wnt16 targets identified noncanonical Wnt/JNK pathway activated transcription factors Fosl2 and Fosl1 as two of the most significantly enriched transcription factors associated with genes activated by Wnt16 while Mef2c was the most significantly enriched transcription factor associated with genes repressed by Wnt16. We also found that a large number of Mef2c targets overlapped with genes down-regulated by Wnt16 and Mef2c itself was transcriptionally repressed by Wnt16 suggesting that Mef2c plays a role in Wnt16-mediated transcriptional regulation.« less
Authors:
ORCiD logo [1] ;  [1] ;  [1] ;  [2] ; ORCiD logo [1]
  1. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate; Univ. of California, Merced, CA (United States). School of Natural Sciences
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Sciences Directorate
Publication Date:
Report Number(s):
LLNL-JRNL-751700
Journal ID: ISSN 0378-1119; 937619
Grant/Contract Number:
AC52-07NA27344; 1R56DK110145
Type:
Published Article
Journal Name:
Gene
Additional Journal Information:
Journal Volume: 675; Journal ID: ISSN 0378-1119
Research Org:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Univ. of California, Merced, CA (United States)
Sponsoring Org:
USDOE; National Inst. of Health (NIH) (United States)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; Wnt16; osteoblasts; RNA-seq; gene expression; Mef2c; bone metabolism; Wnt3a; Wnt5a; Sostc; Wnt signaling
OSTI Identifier:
1460423
Alternate Identifier(s):
OSTI ID: 1476213

Sebastian, Aimy, Hum, Nicholas R., Morfin, Cesar, Murugesh, Deepa K., and Loots, Gabriela G.. Global gene expression analysis identifies Mef2c as a potential player in Wnt16-mediated transcriptional regulation. United States: N. p., Web. doi:10.1016/j.gene.2018.06.079.
Sebastian, Aimy, Hum, Nicholas R., Morfin, Cesar, Murugesh, Deepa K., & Loots, Gabriela G.. Global gene expression analysis identifies Mef2c as a potential player in Wnt16-mediated transcriptional regulation. United States. doi:10.1016/j.gene.2018.06.079.
Sebastian, Aimy, Hum, Nicholas R., Morfin, Cesar, Murugesh, Deepa K., and Loots, Gabriela G.. 2018. "Global gene expression analysis identifies Mef2c as a potential player in Wnt16-mediated transcriptional regulation". United States. doi:10.1016/j.gene.2018.06.079.
@article{osti_1460423,
title = {Global gene expression analysis identifies Mef2c as a potential player in Wnt16-mediated transcriptional regulation},
author = {Sebastian, Aimy and Hum, Nicholas R. and Morfin, Cesar and Murugesh, Deepa K. and Loots, Gabriela G.},
abstractNote = {Wnt16 is a major Wnt ligand involved in the regulation of postnatal bone homeostasis. Previous studies have shown that Wnt16 promotes bone formation and inhibits bone resorption, suggesting that this molecule could be targeted for therapeutic interventions to treat bone thinning disorders such as osteoporosis. However, the molecular mechanisms by which Wnt16 regulates bone metabolism is not yet fully understood. To better understand the molecular mechanisms by which Wnt16 promotes bone formation and to identify the target genes regulated by Wnt16 in osteoblasts, we treated calvarial osteoblasts purified from C57Bl/6 mice with recombinant Wnt16 and profiled the gene expression changes by RNA-seq at 24 h post-treatment. We also compared gene expression profiles of Wnt16-treated osteoblasts to canonical Wnt3a- and non-canonical Wnt5a-treated osteoblasts. This study identified 576 genes differentially expressed in Wnt16-treated osteoblasts compared to sham-treated controls; these included several members of Wnt pathway (Wnt2b, Wnt7b, Wnt11, Axin2, Sfrp2, Sfrp4, Fzd5 etc.) and TGF-β/BMP signaling pathway (Bmp7, Inhba, Inhbb, Tgfb2 etc.). Wnt16 also regulated a large number of genes with known bone phenotypes. We also found that about 37% (215/576) of the Wnt16 targets overlapped with Wnt3a targets and ~15% (86/576) overlapped with Wnt5a targets, suggesting that Wnt16 activates both canonical and non-canonical Wnt signaling targets in osteoblasts. Transcription factor binding motif enrichment analysis in the promoter regions of Wnt16 targets identified noncanonical Wnt/JNK pathway activated transcription factors Fosl2 and Fosl1 as two of the most significantly enriched transcription factors associated with genes activated by Wnt16 while Mef2c was the most significantly enriched transcription factor associated with genes repressed by Wnt16. We also found that a large number of Mef2c targets overlapped with genes down-regulated by Wnt16 and Mef2c itself was transcriptionally repressed by Wnt16 suggesting that Mef2c plays a role in Wnt16-mediated transcriptional regulation.},
doi = {10.1016/j.gene.2018.06.079},
journal = {Gene},
number = ,
volume = 675,
place = {United States},
year = {2018},
month = {7}
}