Abstract:Telomeres protect the ends of our chromosomes and are key to maintaining genomic integrity during cell division and differentiation. However, our knowledge of telomeric chromatin and nucleosome structure at the molecular level is limited. Here, we aimed to define the structure, dynamics as well as properties in solution of the human telomeric nucleosome. We first determined the 2.2 Å crystal structure of a human telomeric nucleosome core particle (NCP) containing 145 bp DNA, which revealed the same helical pat… Show more
“…The connection between histone and DNA dynamics was supported by comparing nucleosomes formed with the 601 sequence to those prepared with a tandem-repeat (TTAGGG) telomere sequence. The TTAGGG nucleosomes displayed a greater range of motions in the cluster network compared to the 601 nucleosomes consistent with previous experiments which showed that telomeric nucleosomes are less stable and wrap DNA less tightly ( Shi et al, 2020b ; Soman et al, 2020 ). Reduced nucleosome stability may translate into more flexible chromatin fibers that in turn enhance the potential for phase separation at telomeres ( Sanulli et al, 2019 ; Farr et al, 2021 ).…”
The eukaryotic genome is packaged into chromatin, a polymer of DNA and histone proteins that regulates gene expression and the spatial organization of nuclear content. The repetitive character of chromatin is diversified into rich layers of complexity that encompass DNA sequence, histone variants and post-translational modifications. Subtle molecular changes in these variables can often lead to global chromatin rearrangements that dictate entire gene programs with far reaching implications for development and disease. Decades of structural biology advances have revealed the complex relationship between chromatin structure, dynamics, interactions, and gene expression. Here, we focus on the emerging contributions of magic-angle spinning solid-state nuclear magnetic resonance spectroscopy (MAS NMR), a relative newcomer on the chromatin structural biology stage. Unique among structural biology techniques, MAS NMR is ideally suited to provide atomic level information regarding both the rigid and dynamic components of this complex and heterogenous biological polymer. In this review, we highlight the advantages MAS NMR can offer to chromatin structural biologists, discuss sample preparation strategies for structural analysis, summarize recent MAS NMR studies of chromatin structure and dynamics, and close by discussing how MAS NMR can be combined with state-of-the-art chemical biology tools to reconstitute and dissect complex chromatin environments.
“…The connection between histone and DNA dynamics was supported by comparing nucleosomes formed with the 601 sequence to those prepared with a tandem-repeat (TTAGGG) telomere sequence. The TTAGGG nucleosomes displayed a greater range of motions in the cluster network compared to the 601 nucleosomes consistent with previous experiments which showed that telomeric nucleosomes are less stable and wrap DNA less tightly ( Shi et al, 2020b ; Soman et al, 2020 ). Reduced nucleosome stability may translate into more flexible chromatin fibers that in turn enhance the potential for phase separation at telomeres ( Sanulli et al, 2019 ; Farr et al, 2021 ).…”
The eukaryotic genome is packaged into chromatin, a polymer of DNA and histone proteins that regulates gene expression and the spatial organization of nuclear content. The repetitive character of chromatin is diversified into rich layers of complexity that encompass DNA sequence, histone variants and post-translational modifications. Subtle molecular changes in these variables can often lead to global chromatin rearrangements that dictate entire gene programs with far reaching implications for development and disease. Decades of structural biology advances have revealed the complex relationship between chromatin structure, dynamics, interactions, and gene expression. Here, we focus on the emerging contributions of magic-angle spinning solid-state nuclear magnetic resonance spectroscopy (MAS NMR), a relative newcomer on the chromatin structural biology stage. Unique among structural biology techniques, MAS NMR is ideally suited to provide atomic level information regarding both the rigid and dynamic components of this complex and heterogenous biological polymer. In this review, we highlight the advantages MAS NMR can offer to chromatin structural biologists, discuss sample preparation strategies for structural analysis, summarize recent MAS NMR studies of chromatin structure and dynamics, and close by discussing how MAS NMR can be combined with state-of-the-art chemical biology tools to reconstitute and dissect complex chromatin environments.
“…This review commenced with a discussion of the classic B-DNA double helix structure; we conclude with two examples of studies on B-DNA deformations from ideality and how data from the PDB has complemented findings from other experimental and theoretical approaches. The B-DNA helix bending in the crystal structure ( 105 ) of a nucleosome comprising human telomeric DNA (with 23 (TTAGGG) repeats), in which the flexible d(TA) step, as well as d(TT) ones, plays an important role in facilitating the bending necessary for wrapping around the histone core, as shown in Figure 9 . DNA bending is related to minor groove width, which has been extensively studied in solution ( 106 ).…”
Section: The Importance Of the Pdb And Ndb For Studies On Dna Structure Flexibility And Functionmentioning
confidence: 99%
“…Clearly much more experimental structural data are needed before we have a comprehensive understanding of DNA flexibility. Figure 9 The structure of the DNA component of a human telomeric nucleosome ( 105 ) , shown in space-filling representation with the two strands in separate colors, together with a magnified view of a typical region of DNA curvature, showing changes from ideality in base pair morphology such as roll, tilt, and twist . …”
Section: The Importance Of the Pdb And Ndb For Studies On Dna Structure Flexibility And Functionmentioning
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“…The accomplishment of genomic DNA activities in eukaryotic cells is propagated from the modulation of dynamic spatiotemporal organization of chromatin, which is achieved through factors including post-translational modifications (PTMs) ( Jenuwein and Allis, 2001 ; Bannister and Kouzarides, 2011 ; Bowman and Poirier, 2014 ; Fenley et al, 2018 ), incorporation histone variants ( Talbert and Henikoff, 2016 ; Martire and Banaszynski, 2020 ), remodelers, and other effector proteins ( Tyagi et al, 2016 ; Armeev et al, 2019 ; Reyes et al, 2021 ). Since the first atomic resolution structure was obtained 24 years ago ( Luger et al, 1997 ), well over a hundred structures of NCPs with different DNA sequences or histone variants and in complex with protein factors have been determined by X-ray diffraction (XRD) and cryogenic electron microscopy (cryo-EM) ( Luger et al, 1997 ; Korolev et al, 2018 ; Zhou et al, 2019 ; Soman et al, 2020 ; Lobbia et al, 2021 ). The atomic structure information opened the door to understanding the molecular basis of genomic DNA regulation processes.…”
Section: Introductionmentioning
confidence: 99%
“…The composition of DNA in nucleosomes is one of the dominant factors dictating the architecture, compactness, and accessibility of chromatin. Varying DNA sequences lead to changes in nucleosome structure, dynamics, positioning, and compactness ( Shaytan et al, 2017 ; Shi et al, 2020b ; Soman et al, 2020 ). For example, our recent study revealed that the telomeric NCPs exhibit higher mobility in both histone N-terminal tails and core regions in comparison with the Widom 601 NCPs ( Shi et al, 2020b ).…”
Dynamics spanning the picosecond-minute time domain and the atomic-subcellular spatial window have been observed for chromatin in vitro and in vivo. The condensed organization of chromatin in eukaryotic cells prevents regulatory factors from accessing genomic DNA, which requires dynamic stabilization and destabilization of structure to initiate downstream DNA activities. Those processes are achieved through altering conformational and dynamic properties of nucleosomes and nucleosome–protein complexes, of which delineating the atomistic pictures is essential to understand the mechanisms of chromatin regulation. In this review, we summarize recent progress in determining chromatin dynamics and their modulations by a number of factors including post-translational modifications (PTMs), incorporation of histone variants, and binding of effector proteins. We focus on experimental observations obtained using high-resolution techniques, primarily including nuclear magnetic resonance (NMR) spectroscopy, Förster (or fluorescence) resonance energy transfer (FRET) microscopy, and molecular dynamics (MD) simulations, and discuss the elucidated dynamics in the context of functional response and relevance.
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