You are hereMarch 4, 2018 | ESCs/iPSCs
Correlating Genome Topology and Gene Regulation during Reprogramming
Review of “Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming” from Nature Genetics by Stuart P. Atkinson
The three-dimensional organization of the genome represents a cell-type specific means to regulate gene transcription; however, we currently lack a detailed understanding of the architectural changes that occur during the generation of induced pluripotent stem cells (iPSCs) due to the inherent inefficiency of the reprogramming process . However, researchers from the laboratories of Ralph Stadhouders, Marc A. Marti-Renom, and Thomas Graf have now applied a highly efficient and synchronous reprogramming system [2, 3] to study how genome topology, chromatin states, and gene expression dynamically change during reprogramming .
To achieve efficient and synchronous reprogramming, the authors expressed reprogramming factors (OSKM) in mouse bone marrow-derived pre-B cells exposed to the C/EBPα transcription factor, leading to nearly 100% reprogramming within 4 to 8 days. The study then utilized a battery of gene expression and chromatin assays to discover that:
- Cell-fate conversion requires the dynamic reorganization of chromatin states and alterations to the active and repressed sub-nuclear compartments
- Compartment changes generally correlate with global gene expression changes
- However, a significant number of genes display altered compartmentalization before changes in gene expression
- Topologically associated domains (TADs), which restrict or facilitate interactions between gene-regulatory elements, remained mostly stable throughout the process
- Alterations to local chromatin insulation strength at TAD borders represented an early reprogramming event and often preceded changes to gene expression
- TAD dynamics displayed signs of elevated plasticity at later stages of reprogramming, as cells attain pluripotency
- Changes in TAD connectivity frequently preceded intra-TAD transcriptional modulation
- Chromatin loops, which allow contacts between regulatory elements controlling gene expression, displayed cell type-specific patterns (B cells vs. iPSCs)
- The presence of looping positively correlated with gene expression
- Overall, C/EBPα and OSKM binding drove topological remodeling of compartmentalization and TAD insulation
- Of note, the technique employed allowed the authors to visualize the stage-specific formation and disassembly of transcription factor interaction hubs during the reprogramming process
Overall, this study highlights the close links between transcription factor-driven genome topology dynamics, chromatin state, and gene expression and highlights a critical role for genome topology in enforcing transcriptional programs and cell fate.
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- Buganim Y, Faddah DA, and Jaenisch R, Mechanisms and models of somatic cell reprogramming. Nat Rev Genet 2013;14:427-39.
- Di Stefano B, Sardina JL, van Oevelen C, et al., C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells. Nature 2013;506:235.
- Di Stefano B, Collombet S, Jakobsen JS, et al., C/EBPα creates elite cells for iPSC reprogramming by upregulating Klf4 and increasing the levels of Lsd1 and Brd4. Nature Cell Biology 2016;18:371.
- Stadhouders R, Vidal E, Serra F, et al., Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming. Nature Genetics 2018;50:238-249.