In culture, MSCs can be readily differentiated into adipocytes, myoblasts, chondrocytes and osteoblasts and have also been shown to have capacity to regenerate cardiac muscle and neurons under induced conditions. During aging, these cell fate decisions are compromised resulting in the production of one tissue at the expense of another (e.g.
BMP/TGF FGF, Wnt) and downstream transcription factors influence decisions of these cells to commit to the formation bone, cartilage, muscle or fat tissue. Under normal physiological conditions, growth factor signaling pathways (e.g. Mesenchymal stromal cells (MSCs) derived from bone marrow are pluripotent progenitor cells that have the capacity to form and regenerate mature connective tissue, however the molecular heterogeneity of these cells is problematic for their wide-spread clinical use. However, for many tissues, the exact contribution of specific histone modifications controlling phenotypic gene expression during the stochastic progression of lineage commitment is not currently well understood. In addition, dynamic changes in histone modifications can influence basal levels of gene expression and regulate expression of specific genes in tissue specification and differentiation programs.
Several profiling studies examining constitutive histone modifications have demonstrated that chromatin states define genomic context for specific cell lineages. Post-translational modifications of histone proteins at lysine, arginine and serine residues dictate the activation or repressive state of a particular gene or genomic region, depending on the presence or absence of acetyl or methyl groups. 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.Īccumulating evidence from genome-wide studies have indicated that histone modifications, chromatin states and tissue-specific transcriptional regulators are inherited from progenitor cells and thus greatly influence phenotypic commitment and cell-specific gene regulation in progeny. 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. Significantly, loss or gain of H3K36me3 was the primary predictor of dynamic changes in temporal gene expression. Additionally, we found that the absence of H3K4me3 modification at promoters defined a subset of osteoblast-specific upregulated genes, indicating acquisition of acetyl modifications drive activation of these genes. We discovered that at commitment, H3K27me3 is removed from genes that are upregulated and is not acquired on downregulated genes. 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. 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. 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. Multipotent mesenchymal stromal cells (MSCs) are critical for regeneration of multiple tissues.
0 kommentar(er)
