Chromatin As Self-returning Walks: From Population to Single Cell and Back

Overview

Journal Biophys Rep (N Y)

Specialty Biophysics

Date 2022 Nov 25

PMID 36425085

Authors

Anne R Shim

Kai Huang

Vadim Backman

Igal Szleifer

Affiliations

Soon will be listed here.

Abstract

With a growing understanding of the chromatin structure, many efforts remain focused on bridging the gap between what is suggested by population-averaged data and what is visualized for single cells. A popular approach to traversing these scales is to fit a polymer model to Hi-C contact data. However, Hi-C is an average of millions to billions of cells, and each cell may not contain all population-averaged contacts. Therefore, we employ a novel approach of summing individual chromosome trajectories-determined by our Self-Returning Random Walk model-to create populations of cells. We allow single cells to consist of disparate structures and reproduce a variety of experimentally relevant contact maps. We show that the amount of shared topology between cells, and their mechanism of formation, changes the population-averaged structure. Therefore, we present a modeling technique that, with few constraints and little oversight, can be used to understand which single-cell chromatin structures underlie population-averaged behavior.

Citing Articles

Formamide denaturation of double-stranded DNA for fluorescence in situ hybridization (FISH) distorts nanoscale chromatin structure.

Shim A, Frederick J, Pujadas E, Kuo T, Ye I, Pritchard J PLoS One. 2024; 19(5):e0301000.

PMID: 38805476 PMC: 11132451. DOI: 10.1371/journal.pone.0301000.

References

Hansen A, Cattoglio C, Darzacq X, Tjian R . Recent evidence that TADs and chromatin loops are dynamic structures. Nucleus. 2017; 9(1):20-32. PMC: 5990973. DOI: 10.1080/19491034.2017.1389365. View

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

Fudenberg G, Imakaev M . FISH-ing for captured contacts: towards reconciling FISH and 3C. Nat Methods. 2017; 14(7):673-678. PMC: 5517086. DOI: 10.1038/nmeth.4329. View

Weinreb C, Raphael B . Identification of hierarchical chromatin domains. Bioinformatics. 2015; 32(11):1601-9. PMC: 4892410. DOI: 10.1093/bioinformatics/btv485. View

Pervolarakis N, Nguyen Q, Williams J, Gong Y, Gutierrez G, Sun P . Integrated Single-Cell Transcriptomics and Chromatin Accessibility Analysis Reveals Regulators of Mammary Epithelial Cell Identity. Cell Rep. 2020; 33(3):108273. PMC: 7874899. DOI: 10.1016/j.celrep.2020.108273. View

Ma H, Naseri A, Reyes-Gutierrez P, Wolfe S, Zhang S, Pederson T . Multicolor CRISPR labeling of chromosomal loci in human cells. Proc Natl Acad Sci U S A. 2015; 112(10):3002-7. PMC: 4364232. DOI: 10.1073/pnas.1420024112. View

Fudenberg G, Abdennur N, Imakaev M, Goloborodko A, Mirny L . Emerging Evidence of Chromosome Folding by Loop Extrusion. Cold Spring Harb Symp Quant Biol. 2018; 82:45-55. PMC: 6512960. DOI: 10.1101/sqb.2017.82.034710. View

Knoch T, Wachsmuth M, Kepper N, Lesnussa M, Abuseiris A, Imam A . The detailed 3D multi-loop aggregate/rosette chromatin architecture and functional dynamic organization of the human and mouse genomes. Epigenetics Chromatin. 2016; 9:58. PMC: 5192698. DOI: 10.1186/s13072-016-0089-x. View

Allahyar A, Vermeulen C, Bouwman B, Krijger P, Verstegen M, Geeven G . Enhancer hubs and loop collisions identified from single-allele topologies. Nat Genet. 2018; 50(8):1151-1160. DOI: 10.1038/s41588-018-0161-5. View

10.

Xu H, Wang J, Liang Y, Fu Y, Li S, Huang J . TriTag: an integrative tool to correlate chromatin dynamics and gene expression in living cells. Nucleic Acids Res. 2020; 48(22):13013-13014. PMC: 7736816. DOI: 10.1093/nar/gkaa1170. View

11.

Shinkai S, Nakagawa M, Sugawara T, Togashi Y, Ochiai H, Nakato R . PHi-C: deciphering Hi-C data into polymer dynamics. NAR Genom Bioinform. 2021; 2(2):lqaa020. PMC: 7671433. DOI: 10.1093/nargab/lqaa020. View

12.

Galitsyna A, Gelfand M . Single-cell Hi-C data analysis: safety in numbers. Brief Bioinform. 2021; 22(6). PMC: 8575028. DOI: 10.1093/bib/bbab316. View

13.

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

14.

Bendandi A, Dante S, Zia S, Diaspro A, Rocchia W . Chromatin Compaction Multiscale Modeling: A Complex Synergy Between Theory, Simulation, and Experiment. Front Mol Biosci. 2020; 7:15. PMC: 7051991. DOI: 10.3389/fmolb.2020.00015. View

15.

Rao S, Huntley M, Durand N, Stamenova E, Bochkov I, Robinson J . A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014; 159(7):1665-80. PMC: 5635824. DOI: 10.1016/j.cell.2014.11.021. View

16.

Ou H, Phan S, Deerinck T, Thor A, Ellisman M, OShea C . ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells. Science. 2017; 357(6349). PMC: 5646685. DOI: 10.1126/science.aag0025. View

17.

Zhang Y, Li T, Preissl S, Amaral M, Grinstein J, Farah E . Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells. Nat Genet. 2019; 51(9):1380-1388. PMC: 6722002. DOI: 10.1038/s41588-019-0479-7. View

18.

Chen B, Gilbert L, Cimini B, Schnitzbauer J, Zhang W, Li G . Dynamic imaging of genomic loci in living human cells by an optimized CRISPR/Cas system. Cell. 2013; 155(7):1479-91. PMC: 3918502. DOI: 10.1016/j.cell.2013.12.001. View

19.

Duan J, Lu G, Xie Z, Lou M, Luo J, Guo L . Genome-wide identification of CRISPR/Cas9 off-targets in human genome. Cell Res. 2014; 24(8):1009-12. PMC: 4123298. DOI: 10.1038/cr.2014.87. View

20.

Fudenberg G, Imakaev M, Lu C, Goloborodko A, Abdennur N, Mirny L . Formation of Chromosomal Domains by Loop Extrusion. Cell Rep. 2016; 15(9):2038-49. PMC: 4889513. DOI: 10.1016/j.celrep.2016.04.085. View