Cell-of-Origin-Specific 3D Genome Structure Acquired during Somatic Cell Reprogramming

• Published in: Cell stem cell Vol. 18; no. 5; pp. 597 - 610
• Main Authors: Krijger, Peter Hugo Lodewijk, Di Stefano, Bruno, de Wit, Elzo, Limone, Francesco, van Oevelen, Chris, de Laat, Wouter, Graf, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.05.2016; Elsevier; Cell Press
• Subjects: Animals; Cellular Reprogramming - genetics; Chromatin - metabolism; Chromosomes, Mammalian - chemistry; Cèl·lules somàtiques; Gene Expression Regulation, Developmental; Genome; Induced Pluripotent Stem Cells - cytology; Mice; Models, Biological; Organ Specificity - genetics
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2016.01.007

Forced expression of reprogramming factors can convert somatic cells into induced pluripotent stem cells (iPSCs). Here we studied genome topology dynamics during reprogramming of different somatic cell types with highly distinct genome conformations. We find large-scale topologically associated domain (TAD) repositioning and alterations of tissue-restricted genomic neighborhoods and chromatin loops, effectively erasing the somatic-cell-specific genome structures while establishing an embryonic stem-cell-like 3D genome. Yet, early passage iPSCs carry topological hallmarks that enable recognition of their cell of origin. These hallmarks are not remnants of somatic chromosome topologies. Instead, the distinguishing topological features are acquired during reprogramming, as we also find for cell-of-origin-dependent gene expression patterns. [Display omitted] •The 3D genome topology of four somatic cell types varies greatly and differs from ESCs•The 3D genomes of iPSCs from different founders and of ESCs are overall highly similar•Early-passage iPSCs show subtle but reproducible founder-dependent 3D differences•The distinctive topology features of iPSCs are acquired during reprogramming Krijger et al. report that the reprogramming of four somatic cell types with highly distinct 3D genomes results in pluripotent cells with largely identical, ESC-like, genome conformations carrying founder-dependent topological hallmarks. The latter are not remnants of somatic chromosome topologies but are acquired during reprogramming in a cell-of-origin-dependent manner.