Abstract
BackgroundChromatin remodeling is crucial for proper programing of developmental gene expression. Recent work provides a dynamic view of post-translational histone modifications during differentiation; however there is little insight on the evolution of combinatorial genome-wide patterns of chromatin marks, excluding an essential aspect of developmental gene regulation.ResultsWe report here a 15-chromatin state Hidden Markov Model which describes changes in chromatin signatures in relation to transcription profiles during differentiation of human pre-adipocytes into adipocytes. We identify nineteen modules of gene expression reflecting multiple waves of transcriptional up- and down-regulation which characterize adipogenic differentiation. From our model, we developed chromatin state matrices fitting each of these transcription modules to show how the complexity and dynamic nature of chromatin signatures relate to expression patterns. Spatial relationships between chromatin states underlie a high-order chromatin organization in differentiating adipocytes. We show the importance of gene expression level in generating diversity in chromatin signatures, and show that the hyper-dynamic nature of H3K4me2/H3K27me3-marked ‘bivalent’ promoter states underlies many of the gene expression patterns associated with adipogenic differentiation.ConclusionsOur results reveal the highly dynamic nature of bivalent promoter states within the adipogenic lineage. The data constitute a valuable resource enabling the assessment of possibilities to alter the adipogenic program.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-1186) contains supplementary material, which is available to authorized users.
Highlights
Chromatin remodeling is crucial for proper programing of developmental gene expression
Adipogenic differentiation is driven by activation of genes encoding transcription factors that synergistically up-regulate target genes involved in adipocyte formation and lipid metabolism [14,15,16], and by chromatin remodeling notably at regulatory elements essential for transcription factor binding [17]
We reveal the importance of gene expression level in generating diversity in chromatin signatures and the hyper-dynamic nature of ‘bivalent’ promoter states during lineage-specific differentiation
Summary
Chromatin remodeling is crucial for proper programing of developmental gene expression. Developmental gene expression entails waves of coordinated transcriptional activation and repression events, which are orchestrated at least in part by the epigenome [1,2,3,4,5], a layer of reversible post-translational modifications on chromatin [6]. These studies invariably indicate that the epigenome is dynamic and that epigenetic modifications are linked to changes in gene expression in a concordant or sometimes seemingly non-concordant manner. The current data portray a dynamic view of enrichment in individual hPTMs [17,18]; insights on the temporal transitions in combinatorial associations of hPTMs during adipogenic differentiation have been missing, leaving out a key aspect of developmental gene regulation
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