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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 difficult to alter suggesting that it is an important component of gene regulation. However, given the multitude of chromatin-associating factors, the mechanisms driving the colocalization of active chromosomal domains and the role of this organization in regulating the transcription program in adipocytes are not clear. Analysis of genome-wide chromosomal associations revealed cell type-specific spatial clustering of adipogenic genes in 3T3-L1 cells. Time course analysis demonstrated that the adipogenic 'hub', sampled by PPARγ and Lpin1, undergoes orchestrated reorganization during adipogenesis. Coupling the dynamics of genome architecture with multiple chromatin datasets indicated that among all the transcription factors (TFs) tested, RXR is central to genome reorganization at the beginning of adipogenesis. Interestingly, at the end of differentiation, the adipogenic hub was shifted to an H3K27me3-repressive environment in conjunction with attenuation of gene transcription. We propose a stage-specific hierarchy for the activity of TFs contributing to the establishment of an adipogenic genome architecture that brings together the adipogenic genetic program. In addition, the repositioning of this network in a H3K27me3-rich environment at the end of differentiation may contribute to the stabilization of gene transcription levels and reduce the developmental plasticity of these specialized cells.

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All sequence data reported in this paper have been deposited at GEO (http://www.ncbi.nlm.nih.gov/geo/) (GSE92475).

SUBMITTER: Sarusi Portuguez A

PROVIDER: S-EPMC5626622 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Sarusi Portuguez Avital A Schwartz Michal M Siersbaek Rasmus R Nielsen Ronni R Sung Myong-Hee MH Mandrup Susanne S Kaplan Tommy T Hakim Ofir O

The FEBS journal 20170816 19

The three dimensional folding of mammalian genomes is cell type specific and difficult to alter suggesting that it is an important component of gene regulation. However, given the multitude of chromatin-associating factors, the mechanisms driving the colocalization of active chromosomal domains and the role of this organization in regulating the transcription program in adipocytes are not clear. Analysis of genome-wide chromosomal associations revealed cell type-specific spatial clustering of ad ...[more]

PMID: 28755519

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Project description:We propose a new computational method for exploring chromatin structural organization based on Markov State Modelling of Hi-C data represented as an interaction network between genomic loci. A Markov process describes the random walk of a traveling probe in the corresponding energy landscape, mimicking the motion of a biomolecule involved in chromatin function. By studying the metastability of the associated Markov State Model upon annealing, the hierarchical structure of individual chromosomes is observed, and corresponding set of structural partitions is identified at each level of hierarchy. Then, the notion of effective interaction between partitions is derived, delineating the overall topology and architecture of chromosomes. Mapping epigenetic data on the graphs of intra-chromosomal effective interactions helps in understanding how chromosome organization facilitates its function. A sketch of whole-genome interactions obtained from the analysis of 539 partitions from all 23 chromosomes, complemented by distributions of gene expression regulators and epigenetic factors, sheds light on the structure-function relationships in chromatin, delineating chromosomal territories, as well as structural partitions analogous to topologically associating domains and active / passive epigenomic compartments. In addition to the overall genome architecture shown by effective interactions, the affinity between partitions of different chromosomes was analyzed as an indicator of the degree of association between partitions in functionally relevant genomic interactions. The overall static picture of whole-genome interactions obtained with the method presented in this work provides a foundation for chromatin structural reconstruction, for the modelling of chromatin dynamics, and for exploring the regulation of genome function. The algorithms used in this study are implemented in a freely available Python package ChromaWalker (https://bitbucket.org/ZhenWahTan/chromawalker).

Dataset Information

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

Database

Publications

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

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