Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome

Yongdae Shin, Yi Che Chang, Daniel S.W. Lee, Joel Berry, David W. Sanders, Pierre Ronceray, Ned S. Wingreen, Mikko Haataja, Clifford P. Brangwynne

Research output: Contribution to journalArticle

98 Scopus citations

Abstract

Phase transitions involving biomolecular liquids are a fundamental mechanism underlying intracellular organization. In the cell nucleus, liquid-liquid phase separation of intrinsically disordered proteins (IDPs) is implicated in assembly of the nucleolus, as well as transcriptional clusters, and other nuclear bodies. However, it remains unclear whether and how physical forces associated with nucleation, growth, and wetting of liquid condensates can directly restructure chromatin. Here, we use CasDrop, a novel CRISPR-Cas9-based optogenetic technology, to show that various IDPs phase separate into liquid condensates that mechanically exclude chromatin as they grow and preferentially form in low-density, largely euchromatic regions. A minimal physical model explains how this stiffness sensitivity arises from lower mechanical energy associated with deforming softer genomic regions. Targeted genomic loci can nonetheless be mechanically pulled together through surface tension-driven coalescence. Nuclear condensates may thus function as mechano-active chromatin filters, physically pulling in targeted genomic loci while pushing out non-targeted regions of the neighboring genome. Video Abstract: Nuclear condensates physically pull in targeted genomic loci while excluding non-targeted regions of the neighboring genome.

Original languageEnglish (US)
Pages (from-to)1481-1491.e13
JournalCell
Volume175
Issue number6
DOIs
StatePublished - Nov 29 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • chromatin
  • condensates
  • gene regulation
  • mechanobiology
  • nuclear mechanics
  • nuclear organization
  • optogenetics
  • phase immiscibility
  • phase separation

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  • Cite this

    Shin, Y., Chang, Y. C., Lee, D. S. W., Berry, J., Sanders, D. W., Ronceray, P., Wingreen, N. S., Haataja, M., & Brangwynne, C. P. (2018). Liquid Nuclear Condensates Mechanically Sense and Restructure the Genome. Cell, 175(6), 1481-1491.e13. https://doi.org/10.1016/j.cell.2018.10.057