4.4 Article

The Chromatin Regulator HMGA1a Undergoes Phase Separation in the Nucleus

Journal

CHEMBIOCHEM
Volume -, Issue -, Pages -

Publisher

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202200450

Keywords

chromatin regulators; HMGA; liquid-liquid phase separation; phase diagrams; protein-DNA interactions

Funding

  1. European Research Council (ERC) under the European Union [803326]
  2. Cancer Research UK Cambridge Institute Core Grant [C9545/A29580]
  3. China Scholarship Council (CSC)
  4. Oppenheimer and Roger Ekins fellowships
  5. Herchel Smith Funds
  6. Wolfson College Junior Research Fellowship
  7. Schmidt Science Fellowship programme
  8. Rhodes Trust
  9. EPSRC Tier-2 capital grant [EP/P020259/1]
  10. European Research Council (ERC) [803326] Funding Source: European Research Council (ERC)

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The study found that HMGA1a can form liquid condensates through phase separation, which is influenced by protein-DNA interactions and post-transcriptional modifications. The C-terminal tail of HMGA1a significantly contributes to its phase separation through electrostatic interactions. This research sheds light on the role of HMGA1 phase separation in regulating chromatin structure.
The protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is promoted by protein-DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through electrostatic interactions via AT hooks 2 and 3. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure.

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