Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming

• Published in: Nature genetics Vol. 50; no. 2; pp. 238 - 249
• Main Authors: Stadhouders, Ralph, Vidal, Enrique, Serra, François, Di Stefano, Bruno, Le Dily, François, Quilez, Javier, Gomez, Antonio, Collombet, Samuel, Berenguer, Clara, Cuartero, Yasmina, Hecht, Jochen, Filion, Guillaume J., Beato, Miguel, Marti-Renom, Marc A., Graf, Thomas
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2018; Nature Publishing Group
• Subjects: 38/91; 45/100; 45/15; 631/136/532; 631/208/176; 631/208/177; 631/208/200; 64/60; Agriculture; Animal Genetics and Genomics; Animals; Binding sites; Binding Sites - genetics; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell fate; Cells, Cultured; Cellular reprogramming; Cellular Reprogramming - genetics; Chromatin; Chromatin Assembly and Disassembly - genetics; Chromosome Structures - genetics; Chromosome Structures - metabolism; Chromosomes; Diploid cell; Dosage Compensation, Genetic - genetics; Female; Gene expression; Gene Expression Regulation; Gene Function; Gene regulation; Genome; Genomes; Genomics; Human Genetics; Induced pluripotent stem cells; Klf4 gene; KLF4 protein; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors - metabolism; Kruppel-Like Transcription Factors - physiology; Mice; Mice, Transgenic; Myc protein; Oct-4 protein; Pluripotency; Principal components analysis; Protein Binding; Somatic cells; Stem cells; Topology; Transcription factors; Transcription Factors - physiology; X Chromosome Inactivation - genetics
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-017-0030-7

Chromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells (PSCs) by the transcription factors (TFs) OCT4, SOX2, KLF4 and MYC offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We have recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells. Here, we used this system to integrate time-resolved changes in genome topology with gene expression, TF binding and chromatin-state dynamics. The results showed that TFs drive topological genome reorganization at multiple architectural levels, often before changes in gene expression. Removal of locus-specific topological barriers can explain why pluripotency genes are activated sequentially, instead of simultaneously, during reprogramming. Together, our results implicate genome topology as an instructive force for implementing transcriptional programs and cell fate in mammals. The authors analyze time-resolved changes in genome topology, gene expression, transcription-factor binding, and chromatin state during iPSC generation. They conclude that 3D genome reorganization generally precedes gene expression changes and that removal of locus-specific topological barriers explains why pluripotency genes are activated sequentially during reprogramming.