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WIREs Comput Mol Sci
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Bridging chromatin structure and function over a range of experimental spatial and temporal scales by molecular modeling

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Abstract Chromatin structure, dynamics, and function are being intensely investigated by a variety of methods, including microscopy, X‐ray diffraction, nuclear magnetic resonance, biochemical crosslinking, chromosome conformation capture, and computation. The modeling helps interpret experimental data and generate configurations and mechanisms related to the three‐dimensional organization and function of the genome. Experimental contact maps, in particular, as obtained by a variety of chromosome conformation capture methods, are of increasing interest due to their implications on genome structure and regulation on many levels. In this perspective, using seven examples from our group's studies, we illustrate how molecular modeling can help interpret such experimental data. Specifically, we show how computed contact maps related to experimental systems can help interpret structures of nucleosomes, chromatin higher‐order folding, domain segregation mechanisms, gene organization, and the effect on chromatin structure of external and internal fiber parameters, such as nucleosome positioning, presence of nucleosome free regions, histone post‐translational modifications, and linker histone binding. We argue that such computations on multiple spatial and temporal scales will be increasingly important for the integration of genomic, epigenomic, and biophysical data on chromatin structure and related cellular processes. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics
The impact of various techniques on the study of chromatin structure and function obtained with the Scopus database and a specific combination of keywords for technique and topic, as detailed in Table S1. (a) Number of articles per year. (b) Impact weighted number of articles; for each article: the total number of citations to date, normalized by number of years since publication. “Comp.” (red curve): computational methods, “Light mic.” (blue): light microscopy techniques, “3C” (black): chromosome conformation capture techniques, “Med. res.” (violet): medium resolution methods, “Cross.” (turquoise): crosslinking techniques, “NMR” (pink): nuclear magnetic resonance techniques, “X‐ray” (orange): X‐ray crystallography techniques, and “Sup. res.” (green): super‐resolution microscopy techniques. Boundary images illustrate chromatin organization levels, from DNA to the nucleosome, nucleosome chains, fibers, and chromosomes. Top and bottom images mark key discoveries obtained by techniques in each category, where the border colors correspond to the technique. Top images, from left to right: Cryo‐EM image showing chromatin repeating subunit, adapted with permission from Ref. ; FISH image showing distribution of chromosome territories in a neuron nucleus, adapted with permission from Ref. ; transmission EM image of in situ cross‐linked nucleosome chains from metaphase chromatin; contact map of 1 Mb segment of human Chr14 at 25 kb resolution, adapted with permission from Ref. ; chromatin fiber of 100 nucleosomes constructed with alternating 25 nucleosomes with acetylated tails and 25 nucleosomes with wild type tails repeated twice, adapted with permission from Ref. . Bottom images, from left to right: X‐ray crystal structure of the nucleosome core particle at 2.8 å resolution, adapted with permission from Ref. ; 1H,15N NMR spectra showing amide resonances of a transcription factor (BPTF PHD) in the absence (black) and presence (red) of a methylated H3 peptide, adapted with permission from Ref. ; and super‐resolution microscopy image of H2B in human fibroblast nucleus showing localization of nucleosomes, adapted with permission from Ref
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Mesoscale modeling studies emphasizing the interplay between experiment (middle ring) and modeling (outer ring), along with crucial internal/external fiber parameters that direct gene folding, as demonstrated for the HOXC gene cluster (center). Clockwise from blue slice: Hierarchical looping in metaphase chromosomes. Computed fiber structures for terminally differentiated cells (1 LH per nucleosome), interphase chromatin (0.5 LH per nucleosome), and metaphase chromatin (no LH), with LHs in turquoise explain nucleosome contacts determined by the EM‐assisted nucleosome interaction capture (EMANIC) technique for metaphase (black bars) and interphase (white bars) chromatin in situ, by the hierarchical looping folding motif, also evident in the accompanying computed contact matrix. Peach slice: LH variant and binding mode dependent fibers. The chromatin fiber topologies (top and side views) are sensitive to different combinations of LH variant, binding mode, and density. The six fibers, from left to right, correspond to: ρ = 1, 100 H1E on‐dyad; ρ = 1, 100 H1E −20°; ρ = 1, 100 H1E +20°; ρ = 1.3, 100 H1E +20° and 30 H1C on‐dyad; ρ = 1.6, 100 H1E +20° and 60 H1C on‐dyad; and ρ = 1.6, 40 H1E +20°, 60 H1E +20°, and 60 H1C −20°, where nucleosomes containing two LH bound are colored in yellow. The crystal structures of a chromatosome with LH (in red) bound on‐dyad (PDBID: 4QLC) and Cryo‐EM chromatosome with LH bound off‐dyad (in green) were used to generate our two binding modes. The cryo‐EM image was adapted with permission from Ref. . Green slice: Enhanced kb contacts by life‐like nucleosome positions. Fibers with life‐like linker lengths and nucleosomes free regions (NFRs) generate many more long‐range kb contacts compared to uniform linker‐length fibers. This is evident by the folded fibers and the associated contact maps, which indicate hierarchical looping in life‐like fibers compared to mostly short‐range interactions in uniform fibers. Yellow slice: Acetylation induced unfolding. Compared to a wild type chromatin (wt), the fiber with acetylated histone tails (Ac) drives global unfolding due to lack of stabilizing internucleosome interactions. The experimental NMR spectra of the core histone H4 K16Q were used to validate the acetylated tail structures obtained by all‐atom molecular dynamics simulations. Adapted with permission from Ref. . The crystal structure of the nucleosome (PDBID: 1KX5) was used to construct dinucleosomes in our multiscale modeling. Violet slice: Gene silencing by hierarchical looping in the GATA‐4 gene. The experimental 3C contacts in 4 different cells (blue, UT cells; violet, DT cells; yellow, HCT116 cells; and light blue, DKO cells) were used as constraints in our GATA‐4 gene model, with image adapted from Ref. . The representative unfolded (left) and folded (right) GATA‐4 gene structures suggest how folding by hierarchical looping would silence the transcription start site (TSS) of the gene. Pink slice: Segregation induced by acetylated domains. Intrinsic compartments of acetylated (Ac)/wild type (wt) segments form at the kb level for a mixed fiber construct (50% wt and 50% Ac) compared to fibers with 100% wt (blue) and 100% Ac (red). Both the Hi‐C contact map of a segment of human Chr3 and our computed contact map of the alternating fiber construct show segregation patterns. The Hi‐C contact map image was adapted with permission from Ref. . Gray inner portion: Folded HOXC gene cluster. All previous internal/external fiber parameters, including nucleosome positions, LH binding positions, and acetylation islands are combined to fold in silico the HOXC gene cluster and reveal a contact hub; see also commentary on our work in Ref. . The contact map of the folded HOXC gene cluster unravels a central interaction between two domains: LH‐rich (top left of contact map) and acetylation‐rich regions (bottom right)
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Our canonical chromatin mesoscale model at center with all its components detailed as follows: (a) Rigid nucleosome core particle (NCP) modeled by 300 discrete charges determined with the DiSCO algorithm, along with flexible histone tails (H3 N‐tail in cyan, H2B N‐tail in magenta, H4 N‐tail in green, H2A N‐tail in yellow, and H2A C‐tail in orange), coarse‐grained as 5 amino acids per bead with charges also determined by DiSCO; (b) Nucleosome with wild type (left) and with folded histone tails (right) containing lysine acetylation modeled by increased stretching, bending, and torsional intertail‐bead force constants by a factor of 100; (c) Linker DNA modeled as a worm‐like chain polymer, coarse‐grained as ~9 bp per bead. The nucleosome repeat lengths (NRLs) of 147 bp plus linker DNA length in bp are modeled by 2, 3, 4, 5, 6, 7, and 8 beads to mimic NRLs = 173, 182, 191, 200, 209, 218, and 226 bp or DNA linker lengths = 26, 35, 44, 53, 62, 71, and 79 bp, respectively; (d) Linker histone (LH) isoforms H1E and H1C, modeled with 22 and 21 beads, respectively (5 amino acids per bead) for the CTDs and 6 beads for GHs with their charges determined by DiSCO; (e) On and off‐dyad (+20° and −20°) binding modes for the LHs; and (f) chromatosome with 2 LH bound (left) and tetranucleosome fiber with a density of 1.5 LH per nucleosome (right), where nucleosomes with 2 LH are colored blue and with 1 LH are colored white
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