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  3. Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system

Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system

  • Sci Adv. 2025 Jan 10;11(2):eadq6652. doi: 10.1126/sciadv.adq6652.
Luay M Almassalha 1 2,  Marcelo Carignano 2 3,  Emily Pujadas Liwag 2 4,  Wing Shun Li 2 3 5,  Ruyi Gong 2 3,  Nicolas Acosta 2 3,  Cody L Dunton 2 3,  Paola Carrillo Gonzalez 2 3,  Lucas M Carter 2 4,  Rivaan Kakkaramadam 2 4,  Martin Kröger 6,  Kyle L MacQuarrie 7 8,  Jane Frederick 2 3,  I Chae Ye 2 3,  Patrick Su 2 3,  Tiffany Kuo 2 4,  Karla I Medina 2 4,  Josh A Pritchard 2 3,  Andrew Skol 7,  Rikkert Nap 2 3,  Masato Kanemaki 9 10 11,  Vinayak Dravid 5 12 13 14 15,  Igal Szleifer 2 3 12,  Vadim Backman 2 3
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Northwestern Memorial Hospital, Chicago, IL 60611, USA.
  • 2 Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL 60208, USA.
  • 3 Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, USA.
  • 4 Interdisciplinary Biological Sciences Graduate Program, Northwestern University, Evanston, IL 60208, USA.
  • 5 Applied Physics Program, Northwestern University, Evanston, IL 60208, USA.
  • 6 Magnetism and Interface Physics and Computational Polymer Physics, Department of Materials, ETH Zurich, CH-8093 Zurich, Switzerland.
  • 7 Stanley Manne Children's Research Institute, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
  • 8 Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  • 9 Department of Chromosome Science, National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan.
  • 10 Graduate Institute for Advanced Studies, SOKENDAI, Yata 1111, Mishima, Shizuoka 411-8540, Japan.
  • 11 Department of Biological Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
  • 12 Department of Chemistry, Northwestern University, Evanston, IL 60208, USA.
  • 13 Materials Science and Engineering, Northwestern University, Evanston, IL 60208, USA.
  • 14 Northwestern University Atomic and Nanoscale Characterization Experimental (NUANCE) Center, Northwestern University, Evanston, IL 60208, USA.
  • 15 International Institute for Nanotechnology (IIN), Northwestern University, Evanston, IL 60208, USA.
PMID: 39792661 DOI: 10.1126/sciadv.adq6652
Abstract

In single cells, variably sized nanoscale chromatin structures are observed, but it is unknown whether these form a cohesive framework that regulates RNA transcription. Here, we demonstrate that the human genome is an emergent, self-assembling, reinforcement learning system. Conformationally defined heterogeneous, nanoscopic packing domains form by the interplay of transcription, nucleosome remodeling, and loop extrusion. We show that packing domains are not topologically associated domains. Instead, packing domains exist across a structure-function life cycle that couples heterochromatin and transcription in situ, explaining how heterochromatin Enzyme inhibition can produce a paradoxical decrease in transcription by destabilizing domain cores. Applied to development and aging, we show the pairing of heterochromatin and transcription at myogenic genes that could be disrupted by nuclear swelling. In sum, packing domains represent a foundation to explore the interactions of chromatin and transcription at the single-cell level in human health.

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