Genome Modeling: From Chromatin Fibers to Genes

Overview

Journal Curr Opin Struct Biol

Date 2022 Dec 28

PMID 36577295

Authors

Stephanie Portillo-Ledesma

Zilong Li

Tamar Schlick

Affiliations

Soon will be listed here.

Abstract

The intricacies of the 3D hierarchical organization of the genome have been approached by many creative modeling studies. The specific model/simulation technique combination defines and restricts the system and phenomena that can be investigated. We present the latest modeling developments and studies of the genome, involving models ranging from nucleosome systems and small polynucleosome arrays to chromatin fibers in the kb-range, chromosomes, and whole genomes, while emphasizing gene folding from first principles. Clever combinations allow the exploration of many interesting phenomena involved in gene regulation, such as nucleosome structure and dynamics, nucleosome-nucleosome stacking, polynucleosome array folding, protein regulation of chromatin architecture, mechanisms of gene folding, loop formation, compartmentalization, and structural transitions at the chromosome and genome levels. Gene-level modeling with full details on nucleosome positions, epigenetic factors, and protein binding, in particular, can in principle be scaled up to model chromosomes and cells to study fundamental biological regulation.

Citing Articles

Phase Space Invaders' podcast episode with Tamar Schlick: a trajectory from mathematics to biology.

Wieczor M, Schlick T Biophys Rev. 2025; 17(1):15-23.

PMID: 40060012 PMC: 11885711. DOI: 10.1007/s12551-025-01271-4.

Incorporating multiscale methylation effects into nucleosome-resolution chromatin models for simulating mesoscale fibers.

Li Z, Portillo-Ledesma S, Janani M, Schlick T J Chem Phys. 2025; 162(9).

PMID: 40047512 PMC: 11888786. DOI: 10.1063/5.0242199.

Advancements and future directions in single-cell Hi-C based 3D chromatin modeling.

Banecki K, Korsak S, Plewczynski D Comput Struct Biotechnol J. 2025; 23:3549-3558.

PMID: 39963420 PMC: 11832020. DOI: 10.1016/j.csbj.2024.09.026.

Integrative Modeling of 3D Genome Organization by Bayesian Molecular Dynamics Simulations with Hi-C Metainference.

Brandani G Methods Mol Biol. 2024; 2856:309-324.

PMID: 39283461 DOI: 10.1007/978-1-0716-4136-1_19.

Multifunctional histone variants in genome function.

Wong L, Tremethick D Nat Rev Genet. 2024; 26(2):82-104.

PMID: 39138293 DOI: 10.1038/s41576-024-00759-1.

References

Conte M, Irani E, Chiariello A, Abraham A, Bianco S, Esposito A . Loop-extrusion and polymer phase-separation can co-exist at the single-molecule level to shape chromatin folding. Nat Commun. 2022; 13(1):4070. PMC: 9279381. DOI: 10.1038/s41467-022-31856-6. View

Bascom G, Kim T, Schlick T . Kilobase Pair Chromatin Fiber Contacts Promoted by Living-System-Like DNA Linker Length Distributions and Nucleosome Depletion. J Phys Chem B. 2017; 121(15):3882-3894. PMC: 6203935. DOI: 10.1021/acs.jpcb.7b00998. View

Davtyan A, Schafer N, Zheng W, Clementi C, Wolynes P, Papoian G . AWSEM-MD: protein structure prediction using coarse-grained physical potentials and bioinformatically based local structure biasing. J Phys Chem B. 2012; 116(29):8494-503. PMC: 3406225. DOI: 10.1021/jp212541y. View

Bascom G, Schlick T . Linking Chromatin Fibers to Gene Folding by Hierarchical Looping. Biophys J. 2017; 112(3):434-445. PMC: 5300842. DOI: 10.1016/j.bpj.2017.01.003. View

Lin X, Qi Y, Latham A, Zhang B . Multiscale modeling of genome organization with maximum entropy optimization. J Chem Phys. 2021; 155(1):010901. PMC: 8253599. DOI: 10.1063/5.0044150. View

Hoencamp C, Dudchenko O, Elbatsh A, Brahmachari S, Raaijmakers J, van Schaik T . 3D genomics across the tree of life reveals condensin II as a determinant of architecture type. Science. 2021; 372(6545):984-989. PMC: 8172041. DOI: 10.1126/science.abe2218. View

Nozaki T, Imai R, Tanbo M, Nagashima R, Tamura S, Tani T . Dynamic Organization of Chromatin Domains Revealed by Super-Resolution Live-Cell Imaging. Mol Cell. 2017; 67(2):282-293.e7. DOI: 10.1016/j.molcel.2017.06.018. View

Zhang R, Erler J, Langowski J . Histone Acetylation Regulates Chromatin Accessibility: Role of H4K16 in Inter-nucleosome Interaction. Biophys J. 2016; 112(3):450-459. PMC: 5300776. DOI: 10.1016/j.bpj.2016.11.015. View

Di Pierro M . Inner workings of gene folding. Proc Natl Acad Sci U S A. 2019; 116(11):4774-4775. PMC: 6421469. DOI: 10.1073/pnas.1900875116. View

10.

Bascom G, Myers C, Schlick T . Mesoscale modeling reveals formation of an epigenetically driven HOXC gene hub. Proc Natl Acad Sci U S A. 2019; 116(11):4955-4962. PMC: 6421463. DOI: 10.1073/pnas.1816424116. View

11.

Jung J, Nishima W, Daniels M, Bascom G, Kobayashi C, Adedoyin A . Scaling molecular dynamics beyond 100,000 processor cores for large-scale biophysical simulations. J Comput Chem. 2019; 40(21):1919-1930. PMC: 7153361. DOI: 10.1002/jcc.25840. View

12.

Li Z, Kono H . Investigating the Influence of Arginine Dimethylation on Nucleosome Dynamics Using All-Atom Simulations and Kinetic Analysis. J Phys Chem B. 2018; 122(42):9625-9634. DOI: 10.1021/acs.jpcb.8b05067. View

13.

Dignon G, Zheng W, Kim Y, Best R, Mittal J . Sequence determinants of protein phase behavior from a coarse-grained model. PLoS Comput Biol. 2018; 14(1):e1005941. PMC: 5798848. DOI: 10.1371/journal.pcbi.1005941. View

14.

Lieberman-Aiden E, van Berkum N, Williams L, Imakaev M, Ragoczy T, Telling A . Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009; 326(5950):289-93. PMC: 2858594. DOI: 10.1126/science.1181369. View

15.

Fu I, Geacintov N, Broyde S . Molecular dynamics simulations reveal how H3K56 acetylation impacts nucleosome structure to promote DNA exposure for lesion sensing. DNA Repair (Amst). 2021; 107:103201. PMC: 8526387. DOI: 10.1016/j.dnarep.2021.103201. View

16.

Rajagopalan M, Balasubramanian S, Ioshikhes I, Ramaswamy A . Structural dynamics of nucleosome mediated by acetylations at H3K56 and H3K115,122. Eur Biophys J. 2016; 46(5):471-484. DOI: 10.1007/s00249-016-1191-5. View

17.

Rao S, Huang S, St Hilaire B, Engreitz J, Perez E, Kieffer-Kwon K . Cohesin Loss Eliminates All Loop Domains. Cell. 2017; 171(2):305-320.e24. PMC: 5846482. DOI: 10.1016/j.cell.2017.09.026. View

18.

Grigoryev S, Bascom G, Buckwalter J, Schubert M, Woodcock C, Schlick T . Hierarchical looping of zigzag nucleosome chains in metaphase chromosomes. Proc Natl Acad Sci U S A. 2016; 113(5):1238-43. PMC: 4747710. DOI: 10.1073/pnas.1518280113. View

19.

Portillo-Ledesma S, Tsao L, Wagley M, Lakadamyali M, Cosma M, Schlick T . Nucleosome Clutches are Regulated by Chromatin Internal Parameters. J Mol Biol. 2020; 433(6):166701. PMC: 7988292. DOI: 10.1016/j.jmb.2020.11.001. View

20.

Conte M, Fiorillo L, Bianco S, Chiariello A, Esposito A, Nicodemi M . Polymer physics indicates chromatin folding variability across single-cells results from state degeneracy in phase separation. Nat Commun. 2020; 11(1):3289. PMC: 7335158. DOI: 10.1038/s41467-020-17141-4. View