Epigenetic Mechanisms Mediating Cell State Transitions in Chondrocytes

Wülling, Manuela; Neu, Christoph;
Affiliation
Developmental Biology, Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany
Thiesen, Andrea M.; Kitanovski, Simo;
GND
1234190257
Affiliation
Bioinformatics and Computational Biophysics, Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany 3
Cao, Yingying;
LSF
55857
Affiliation
Bioinformatics and Computational Biophysics, Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany 3
Lange, Anja; Westendorf, Astrid M.;
GND
1021044180
ORCID
0000-0003-2973-7869
LSF
16263
Affiliation
Bioinformatics and Computational Biophysics, Centre for Medical Biotechnology, University Duisburg-Essen, Essen, Germany
Hoffmann, Daniel; Vortkamp, Andrea
Epigenetic modifications play critical roles in regulating cell lineage differentiation, but the epigenetic mechanisms guiding specific differentiation steps within a cell lineage have rarely been investigated. To decipher such mechanisms, we used the defined transition from proliferating (PC) into hypertrophic chondrocytes (HC) during endochondral ossification as a model. We established a map of activating and repressive histone modifications for each cell type. ChromHMM state transition analysis and Pareto-based integration of differential levels of mRNA and epigenetic marks revealed that differentiation-associated gene repression is initiated by the addition of H3K27me3 to promoters still carrying substantial levels of activating marks. Moreover, the integrative analysis identified genes specifically expressed in cells undergoing the transition into hypertrophy. Investigation of enhancer profiles detected surprising differences in enhancer number, location, and transcription factor binding sites between the two closely related cell types. Furthermore, cell type–specific upregulation of gene expression was associated with increased numbers of H3K27ac peaks. Pathway analysis identified PC-specific enhancers associated with chondrogenic genes, whereas HC-specific enhancers mainly control metabolic pathways linking epigenetic signature to biological functions. Since HC-specific enhancers show a higher conservation in postnatal tissues, the switch to metabolic pathways seems to be a hallmark of differentiated tissues. Surprisingly, the analysis of H3K27ac levels at super-enhancers revealed a rapid adaption of H3K27ac occupancy to changes in gene expression, supporting the importance of enhancer modulation for acute alterations in gene expression.

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