Chromatin conformation, gene transcription, and nucleosome remodeling as an emergent system
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.
Authors
- Paola Carrillo Gonzalez (ORCID: https://orcid.org/0000-0003-2988-0913)
- Vadim Backman (ORCID: https://orcid.org/0000-0003-1981-1818)
- Ruyi Gong (ORCID: https://orcid.org/0009-0004-1008-2844)
- Marcelo A. Carignano
- Masato T. Kanemaki (ORCID: https://orcid.org/0000-0002-7657-1649)
- Kyle L. MacQuarrie
- Cody L. Dunton (ORCID: https://orcid.org/0000-0002-0909-9647)
- Vinayak P. Dravid (ORCID: https://orcid.org/0000-0002-6007-3063)
- Nicolas Acosta (ORCID: https://orcid.org/0009-0008-9278-7491)
- Emily M. Pujadas-Liwag (ORCID: https://orcid.org/0000-0002-3520-835X)
- Martin Kröger (ORCID: https://orcid.org/0000-0003-1402-6714)
- I Chae Ye (ORCID: https://orcid.org/0000-0002-5072-8900)
- Andrew D. Skol (ORCID: https://orcid.org/0009-0005-7530-8127)
- Patrick Su (ORCID: https://orcid.org/0000-0002-6051-0462)
- Luay M. Almassalha (ORCID: https://orcid.org/0000-0001-9355-7681)
- Wing Shun Li (ORCID: https://orcid.org/0000-0001-9308-3674)
- Rikkert J. Nap
- Tiffany Kuo (ORCID: https://orcid.org/0009-0008-3599-4443)
- Igal Szleifer
- Lucas Carter (ORCID: https://orcid.org/0000-0003-0385-9833)
- Jane Frederick (ORCID: https://orcid.org/0000-0003-3007-9197)
- Rivaan Kakkaramadam (ORCID: https://orcid.org/0009-0003-3005-0164)
- Josh Pritchard
- Karla Medina (ORCID: https://orcid.org/0000-0001-7182-2026)
Institutions
- Northwestern University (US)
- National Institute of Genetics (JP)
- Lurie Children's Hospital (US)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- ETH Zurich (CH)
- Northwestern Memorial Hospital (US)
- Lurie Children's Hospital (US)
- The University of Tokyo (JP)
Publication Details
- Journal
- Science Advances
- Published
- 2025-01-10
- DOI
- https://doi.org/10.1126/sciadv.adq6652
- Citations
- 24
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 19.34
Funders
- CURE Childhood Cancer
- Northwestern University
- National Institutes of Health
- Feinberg School of Medicine
- National Center for Advancing Translational Sciences
- Hyundai Hope On Wheels