Chromatin dynamics regulate mesenchymal stem cell lineage specification and differentiation to osteogenesis

Hai Wu, Jonathan A.R. Gordon, Troy W. Whitfield, Phillip W.L. Tai, Andre J. van Wijnen, Janet L. Stein, Gary S. Stein, Jane B. Lian

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Multipotent mesenchymal stromal cells (MSCs) are critical for regeneration of multiple tissues. Epigenetic mechanisms are fundamental regulators of lineage specification and cell fate, and as such, we addressed the question of which epigenetic modifications characterize the transition of nascent MSCs to a tissue specific MSC-derived phenotype. By profiling the temporal changes of seven histone marks correlated to gene expression during proliferation, early commitment, matrix deposition, and mineralization stages, we identified distinct epigenetic mechanisms that regulate transcriptional programs necessary for tissue-specific phenotype development. Patterns of stage-specific enrichment of histone modifications revealed distinct modes of repression and activation of gene expression that would not be detected using single endpoint analysis. We discovered that at commitment, H3K27me3 is removed from genes that are upregulated and is not acquired on downregulated genes. Additionally, we found that the absence of H3K4me3 modification at promoters defined a subset of osteoblast-specific upregulated genes, indicating that acquisition of acetyl modifications drive activation of these genes. Significantly, loss or gain of H3K36me3 was the primary predictor of dynamic changes in temporal gene expression. Using unsupervised pattern discovery analysis the signature of osteogenic-related histone modifications identified novel functional cis regulatory modules associated with enhancer regions that control tissue-specific genes. Our work provides a cornerstone to understand the epigenetic regulation of transcriptional programs that are important for MSC lineage commitment and lineage, as well as insights to facilitate MSC-based therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)438-449
Number of pages12
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1860
Issue number4
DOIs
StatePublished - Apr 1 2017

Keywords

  • ChIP-Seq
  • Chromatin
  • Epigenetics
  • Epigenomics
  • Gene expression
  • Mesenchymal stromal cells
  • Osteoblast

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Wu, H., Gordon, J. A. R., Whitfield, T. W., Tai, P. W. L., van Wijnen, A. J., Stein, J. L., Stein, G. S., & Lian, J. B. (2017). Chromatin dynamics regulate mesenchymal stem cell lineage specification and differentiation to osteogenesis. Biochimica et Biophysica Acta - Gene Regulatory Mechanisms, 1860(4), 438-449. https://doi.org/10.1016/j.bbagrm.2017.01.003