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Hierarchical role for transcription factors and chromatin structure in genome organization along adipogenesis

ABSTRACT: The three dimensional folding of mammalian genomes is cell-type specific and hard to convert suggesting that it is an important layer of gene regulation. Analysis of genome-wide chromosomal associations revealed adipogenesis-specific spatial clustering of adipogenic genes in 3T3-L1 cells. High temporal resolution analysis revealed that the adipogenic "hub", sampled by pparg and Lpin1, undergoes orchestrated reorganization along adipogenesis. Coupling the dynamics of genome architecture with multiple chromatin datasets, points that among all transcription factors tested, RXR is central in genome reorganization at the beginning of adipogenesis. Interestingly, at the end of differentiation the adipogenic hub is shifted to H3K27me3 repressive environment in conjunction with attenuation of gene transcription. Together, we propose stage-specific hierarchy among the orchestra of transcription factors contributing to the establishment of the adipogenic genome architecture that brings together the adipogenic genetic program. In addition, the repositioning to H3K27me3 environment in the end of the differentiation may contribute to stabilize gene expression levels and diminish the developmental plasticity of the specialize cell.

ORGANISM(S): Mus musculus

PROVIDER: GSE92475 | GEO | 2017/07/31

SECONDARY ACCESSION(S): PRJNA357639

REPOSITORIES: GEO

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Project description:Background: Obesity is characterized as a disease that directly affects the whole-body metabolism and is associated with excess fat mass and several related comorbidities. Dynamics of the adipocyte hypertrophy and hyperplasia play an important role in health and disease, especially in obesity. Human adipose-derived stem cells (hASC) represent an important source for understanding the entire adipogenic differentiation process. However, little is known about the triggering step of adipogenesis in hASC. Here, we performed a proteogenomic approach for understanding the protein abundance alterations expression changes during the initiation of the adipogenic differentiation process. Methods: hASC were isolated from adipose tissue from three donors, characterized and expanded. Cells were cultured for 24 hours in adipogenic differentiation medium followed to protein extraction. We used shotgun proteomics to compare the proteomic profile of 24h-adipogenic differentiated and undifferentiated hASC. Besides, we used our previously next-generation sequencing data (RNA-seq) from the total and polysomal mRNA fractions of hASC to study post-transcriptional regulation during the initial steps of adipogenesis. Results: We identified a total of 3,.420 proteins out of and 48,.336 peptides, being 92 exclusively identified proteins in the undifferentiated hASC and 53 exclusive proteins in 24h-differentiated cells. Using a stringent criterion, we identified 33 differentially abundant proteins when compare 24h-differentiated versus undifferentiated hASC (14 upregulated and 19 downregulated, respectively). Among the upregulated proteins, we shortlist identified several adipogenic-related proteins. Combined analysis of the proteome and the transcriptome allowed the identification of positive correlation coefficients between proteins and mRNAs. Conclusions: These results demonstrate a specific proteome profile related to adipogenesis at the very beginning (24h) of the differentiation process in hASC, which represents an important piece for a better understanding of human adipogenesis and obesity. In addition, the adipogenic differentiation is fine-tuning regulated at transcriptional, post-transcriptional and post-translational levels.

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Hierarchical role for transcription factors and chromatin structure in genome organization along adipogenesis

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