Forced unraveling of chromatin fibers with nonuniform linker DNA lengths

The chromatin fiber undergoes significant structural changes during the cell's life cycle to modulate DNA accessibility. Detailed mechanisms of such structural transformations of chromatin fibers as affected by various internal and external conditions such as the ionic conditions of the medium, the linker DNA length, and the presence of linker histones, constitute an open challenge. Here we utilize Monte Carlo (MC) simulations of a coarse grained model of chromatin with nonuniform linker DNA lengths as found in vivo to help explain some aspects of this challenge. We investigate the unfolding mechanisms of chromatin fibers with alternating linker lengths of 26-62 bp and 44-79 bp using a series of end-to-end stretching trajectories with and without linker histones and compare results to uniform-linker-length fibers. We find that linker histones increase overall resistance of nonuniform fibers and lead to fiber unfolding with superbeads-on-a-string cluster transitions. Chromatin fibers with nonuniform linker DNA lengths display a more complex, multi-step yet smoother process of unfolding compared to their uniform counterparts, likely due to the existence of a more continuous range of nucleosome-nucleosome interactions. This finding echoes the theme that some heterogeneity in fiber component is biologically advantageous.

[1]  Donald E. Olins,et al.  Spheroid Chromatin Units (ν Bodies) , 1974, Science.

[2]  M. Levitt,et al.  Theoretical studies of enzymic reactions: dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. , 1976, Journal of molecular biology.

[3]  A Klug,et al.  Solenoidal model for superstructure in chromatin. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. O. Thomas,et al.  Exchange of histone H1 between segments of chromatin. , 1981, Journal of molecular biology.

[5]  R. Kornberg,et al.  Variable center to center distance of nucleosomes in chromatin. , 1982, Journal of molecular biology.

[6]  H. Zentgraf,et al.  Differences of supranucleosomal organization in different kinds of chromatin: cell type-specific globular subunits containing different numbers of nucleosomes , 1984, The Journal of cell biology.

[7]  L. Bergman,et al.  Nuclease digestion of circular TRP1ARS1 chromatin reveals positioned nucleosomes separated by nuclease-sensitive regions. , 1984, Journal of molecular biology.

[8]  J. B. Rattner,et al.  The higher-order structure of chromatin: evidence for a helical ribbon arrangement , 1984, The Journal of cell biology.

[9]  B D Athey,et al.  Chromatin fibers are left-handed double helices with diameter and mass per unit length that depend on linker length. , 1986, Biophysical journal.

[10]  J. Widom,et al.  A relationship between the helical twist of DNA and the ordered positioning of nucleosomes in all eukaryotic cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A J Koster,et al.  Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. Bustamante,et al.  Pulling chromatin fibers: computer simulations of direct physical micromanipulations. , 2000, Journal of molecular biology.

[13]  C. Bustamante,et al.  Pulling a single chromatin fiber reveals the forces that maintain its higher-order structure. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[14]  M. Hendzel,et al.  Rapid exchange of histone H1.1 on chromatin in living human cells , 2000, Nature.

[15]  Tom Misteli,et al.  Dynamic binding of histone H1 to chromatin in living cells , 2000, Nature.

[16]  Jan Greve,et al.  Unfolding individual nucleosomes by stretching single chromatin fibers with optical tweezers , 2001, Nature Structural Biology.

[17]  T Schlick,et al.  Modeling salt-mediated electrostatics of macromolecules: the discrete surface charge optimization algorithm and its application to the nucleosome. , 2001, Biopolymers.

[18]  S. Jackson,et al.  Suppression of homologous recombination by the Saccharomyces cerevisiae linker histone. , 2003, Molecular cell.

[19]  Donald E. Olins,et al.  Chromatin history: our view from the bridge , 2003, Nature Reviews Molecular Cell Biology.

[20]  Qing Zhang,et al.  Constructing irregular surfaces to enclose macromolecular complexes for mesoscale modeling using the discrete surface charge optimization (DISCO) algorithm , 2003, J. Comput. Chem..

[21]  Helmut Schiessel,et al.  Nucleosome interactions in chromatin: fiber stiffening and hairpin formation. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[22]  T. Schlick,et al.  Electrostatic mechanism of nucleosomal array folding revealed by computer simulation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Tamar Schlick,et al.  Flexible histone tails in a new mesoscopic oligonucleosome model. , 2006, Biophysical journal.

[24]  Louise Fairall,et al.  EM measurements define the dimensions of the "30-nm" chromatin fiber: evidence for a compact, interdigitated structure. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Daban,et al.  Highly compact folding of chromatin induced by cellular cation concentrations. Evidence from atomic force microscopy studies in aqueous solution , 2006, European Biophysics Journal.

[26]  Jörg Langowski,et al.  Monte Carlo simulation of chromatin stretching. , 2006, Physical review. E, Statistical, nonlinear, and soft matter physics.

[27]  K. V. van Holde,et al.  Chromatin fiber structure: Where is the problem now? , 2007, Seminars in cell & developmental biology.

[28]  Jean-Marc Victor,et al.  An All-Atom Model of the Chromatin Fiber Containing Linker Histones Reveals a Versatile Structure Tuned by the Nucleosomal Repeat Length , 2007, PloS one.

[29]  D. Rhodes,et al.  Nucleosome repeat length and linker histone stoichiometry determine chromatin fiber structure , 2008, Proceedings of the National Academy of Sciences.

[30]  Achilleas S Frangakis,et al.  Analysis of cryo-electron microscopy images does not support the existence of 30-nm chromatin fibers in mitotic chromosomes in situ , 2008, Proceedings of the National Academy of Sciences.

[31]  R. Roeder,et al.  30 nm chromatin fibre decompaction requires both H4-K16 acetylation and linker histone eviction. , 2008, Journal of molecular biology.

[32]  J. Chin,et al.  A Method for Genetically Installing Site-Specific Acetylation in Recombinant Histones Defines the Effects of H3 K56 Acetylation , 2009, Molecular cell.

[33]  Tamar Schlick,et al.  Evidence for heteromorphic chromatin fibers from analysis of nucleosome interactions , 2009, Proceedings of the National Academy of Sciences.

[34]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[35]  Colin Logie,et al.  Single-molecule force spectroscopy reveals a highly compliant helical folding for the 30-nm chromatin fiber , 2009, Nature Structural &Molecular Biology.

[36]  Tamar Schlick,et al.  Mesoscale simulations of two nucleosome-repeat length oligonucleosomes. , 2009, Physical chemistry chemical physics : PCCP.

[37]  J. Langowski,et al.  Rigid assembly and Monte Carlo models of stable and unstable chromatin structures: the effect of nucleosomal spacing , 2010 .

[38]  Kazuhiro Maeshima,et al.  Chromatin structure: does the 30-nm fibre exist in vivo? , 2010, Current opinion in cell biology.

[39]  Tamar Schlick,et al.  Modeling studies of chromatin fiber structure as a function of DNA linker length. , 2010, Journal of molecular biology.

[40]  H. Szerlong,et al.  Nucleosome distribution and linker DNA: connecting nuclear function to dynamic chromatin structure. , 2011, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[41]  Gero Wedemann,et al.  Force spectroscopy of chromatin fibers: extracting energetics and structural information from Monte Carlo simulations. , 2011, Biopolymers.

[42]  Tamar Schlick,et al.  The effect of linker histone's nucleosome binding affinity on chromatin unfolding mechanisms. , 2011, Biophysical journal.

[43]  S. Grigoryev Nucleosome spacing and chromatin higher-order folding , 2012, Nucleus.

[44]  Michael Schubert,et al.  Short nucleosome repeats impose rotational modulations on chromatin fibre folding , 2012, The EMBO journal.

[45]  Benjamin S. Freedman,et al.  Histone H1 compacts DNA under force and during chromatin assembly , 2012, Molecular biology of the cell.

[46]  Tamar Schlick,et al.  Crucial role of dynamic linker histone binding and divalent ions for DNA accessibility and gene regulation revealed by mesoscale modeling of oligonucleosomes , 2012, Nucleic acids research.

[47]  T. Schlick,et al.  Insights into chromatin fibre structure by in vitro and in silico single-molecule stretching experiments. , 2013, Biochemical Society transactions.

[48]  K. Maeshima,et al.  Chromatin as dynamic 10-nm fibers , 2014, Chromosoma.

[49]  Tamar Schlick,et al.  Chromatin fiber polymorphism triggered by variations of DNA linker lengths , 2014, Proceedings of the National Academy of Sciences.

[50]  D. Mathur Biology-inspired AMO physics , 2015 .

[51]  L. Szekely,et al.  HHV-8 encoded LANA-1 alters the higher organization of the cell nucleus , 2007, Molecular Cancer.