New insight into mitosis: small loops endure where larger structures fall away
In a surprising turn for how we understand cell division, MIT researchers have found that tiny 3D loops in the genome persist—or even strengthen—during mitosis, the process by which a cell copies its DNA and divides into two daughter cells. This discovery challenges the long-held view that the genome becomes a blank slate during mitosis and that the intricate 3D organization essential for gene regulation is lost until the cell reassembles its structure in G1. By applying a higher-resolution genome-mapping technique, the team uncovered a steady presence of microcompartments—small, highly connected loops that couple regulatory elements with genes—even as chromosomes compact for division.
The research, published in Nature Structural and Molecular Biology, shows that while large-scale genome features such as A/B compartments and topologically associating domains (TADs) disappear during mitosis, these tiny regulatory loops endure, and may become more pronounced as the genome tightens. This suggests that cells carry a thread of regulatory memory through division, helping to preserve the history of gene interactions from one cell cycle to the next.
Microcompartments: a new piece of the regulatory puzzle
Historically, Hi-C-based methods offered a view of genome organization but lacked the resolution to detect fine-grained regulatory interactions. In 2023, Hansen and colleagues introduced Region-Capture Micro-C (RC-MC), a high-resolution technique that targets small genome segments and uses a different enzyme to create uniformly sized fragments. This approach revealed microcompartments—nested, highly connected loops formed when enhancers and promoters near each other engage.
During mitosis, when chromosomes condense to facilitate equal separation into daughter cells, larger structural domains dissipate. The MIT team initially expected microcompartments to disappear as well. Instead, they observed that these microloops persist and even strengthen as the division proceeds. This finding provides a potential mechanism for the brief transcriptional spike observed toward the end of mitosis, aligning with a renewed, albeit transient, gene-activation window as cells transition into G1.
How microcompartments might influence gene activity
The study links genome structure directly to function: microcompartments appear near genes that show a transcriptional uptick during mitosis, suggesting that compaction helps bring together enhancers and promoters in ways that briefly elevate gene expression. As cells exit mitosis and enter the G1 phase, many of these loops weaken or vanish, indicating that the cell refines these interactions during the restart of gene regulation after division.
Broader implications for biology and medicine
By illuminating how regulatory loops survive division, this work offers a bridge between chromosome architecture and gene control across cell cycles. Understanding this continuum could influence how researchers think about developmental biology, cancer, and regenerative medicine, where misregulation of genome organization and transcription is common. The study also raises new questions: what determines which microcompartments persist into G1, and how do cell size and shape influence the 3D genome during division?
Looking ahead: questions and next steps
Hansen, Banigan, and collaborators are exploring how shifts in cell geometry affect microcompartment formation and stability, and how these structures contribute to faithful gene expression after mitosis. The researchers also aim to uncover the precise molecular mechanisms governing microcompartment formation during chromatin compaction and to map how these loops are selectively retained or pruned when cells re-enter the gene-expression program in G1.
As techniques like RC-MC continue to evolve, our view of the genome’s dynamic choreography during division will become clearer, with potential to reveal new targets for therapies that modulate gene regulation in disease. The discovery that tiny regulatory loops endure through mitosis invites a more nuanced narrative: mitosis is not a total reset, but rather a clever, selective reorganization that preserves essential regulatory circuitry for the cell’s next cycle.
