Mesoscale Modeling and Single-Nucleosome Tracking Reveal Remodeling of Clutch Folding and Dynamics in Stem Cell Differentiation
Pablo Aurelio Gómez-García,
Stephanie Portillo-Ledesma,
Maria Victoria Neguembor,
Martina Pesaresi,
Walaa Oweis,
Talia Rohrlich,
Stefan Wieser,
Eran Meshorer,
Tamar Schlick,
Maria Pia Cosma,
Melike Lakadamyali
Affiliations
Pablo Aurelio Gómez-García
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain; Institute of Photonic Sciences (ICFO), The Barcelona Institute of Science and Technology (BIST), Castelldefels, 08860 Barcelona, Spain
Stephanie Portillo-Ledesma
Department of Chemistry, 1021 Silver Center, 100 Washington Square East, New York University, New York, NY 10003, USA
Maria Victoria Neguembor
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain
Martina Pesaresi
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain
Walaa Oweis
Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel
Talia Rohrlich
Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel
Stefan Wieser
Institute of Photonic Sciences (ICFO), The Barcelona Institute of Science and Technology (BIST), Castelldefels, 08860 Barcelona, Spain
Eran Meshorer
Department of Genetics, The Alexander Silberman Institute of Life Sciences, Faculty of Science, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel; The Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel
Tamar Schlick
Department of Chemistry, 1021 Silver Center, 100 Washington Square East, New York University, New York, NY 10003, USA; Courant Institute of Mathematical Sciences, 251 Mercer Street, New York University, New York, NY 10012, USA; NYU-ECNU Center for Computational Chemistry at New York University Shanghai, 340 Geography Building, 3663 North Zhongshan Road, Shanghai 3663, China
Maria Pia Cosma
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain; Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China; CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Corresponding author
Melike Lakadamyali
Perelman School of Medicine, Department of Physiology, University of Pennsylvania, Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA; Perelman School of Medicine, Department of Cell and Developmental Biology, University of Pennsylvania, Biomedical Research Building, 421 Curie Boulevard, Philadelphia, PA 19104, USA; Corresponding author
Summary: Nucleosomes form heterogeneous groups in vivo, named clutches. Clutches are smaller and less dense in mouse embryonic stem cells (ESCs) compared to neural progenitor cells (NPCs). Using coarse-grained modeling of the pluripotency Pou5f1 gene, we show that the genome-wide clutch differences between ESCs and NPCs can be reproduced at a single gene locus. Larger clutch formation in NPCs is associated with changes in the compaction and internucleosome contact probability of the Pou5f1 fiber. Using single-molecule tracking (SMT), we further show that the core histone protein H2B is dynamic, and its local mobility relates to the structural features of the chromatin fiber. H2B is less stable and explores larger areas in ESCs compared to NPCs. The amount of linker histone H1 critically affects local H2B dynamics. Our results have important implications for how nucleosome organization and H2B dynamics contribute to regulate gene activity and cell identity.
