Mesoscale Modeling and Single-Nucleosome Tracking Reveal Remodeling of Clutch Folding and Dynamics in Stem Cell Differentiation

• Published in: Cell reports (Cambridge) 2021-01, Vol.34 (2), p.108614-108614, Article 108614
• Main Authors: Gómez-García, Pablo Aurelio, Portillo-Ledesma, Stephanie, Neguembor, Maria Victoria, Pesaresi, Martina, Oweis, Walaa, Rohrlich, Talia, Wieser, Stefan, Meshorer, Eran, Schlick, Tamar, Cosma, Maria Pia, Lakadamyali, Melike
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Chromatin - metabolism; chromatin dynamics; chromatin structure; Humans; mesoscale modeling; Mice; Models, Molecular; Nucleosomes - metabolism; single molecule tracking; Stem Cells - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108614

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. [Display omitted] •Mesoscale modeling of the Pou5f1 gene shows cell-type-specific nucleosome clutch patterns•H2B dynamics is cell-type specific and correlates with nucleosome clutch patterns•Linker histone H1 plays an important role in regulating H2B dynamics Gómez-García et al. show that the Pou5f1 gene folds into nucleosome clutches, with larger clutches in differentiated cells than in stem cells. These clutch changes are accompanied by enhanced hierarchical looping in differentiated cells. H2B dynamics is cell-type specific, correlates with clutch patterns, and is regulated by linker histone H1.