In silico evidence for sequence-dependent nucleosome sliding

Significance The dynamic compaction of DNA into chromatin is essential for gene expression. Errors during compaction are associated with numerous diseases. Several molecular factors are known to affect chromatin dynamics, but their relative importance and the interplay between them are poorly understood. A detailed molecular model is used here to examine chromatin dynamics at the level of its most fundamental building block, namely the nucleosome. Nucleosome dynamics are demonstrated to be encoded in the DNA sequence itself, and key fundamental factors are uncovered that can significantly alter these dynamics at the molecular level. The results serve to complete a hitherto unavailable description of nucleosome dynamics by introducing previously unappreciated molecular processes, with the potential to influence macroscopic chromatin structure and genetics. Nucleosomes represent the basic building block of chromatin and provide an important mechanism by which cellular processes are controlled. The locations of nucleosomes across the genome are not random but instead depend on both the underlying DNA sequence and the dynamic action of other proteins within the nucleus. These processes are central to cellular function, and the molecular details of the interplay between DNA sequence and nucleosome dynamics remain poorly understood. In this work, we investigate this interplay in detail by relying on a molecular model, which permits development of a comprehensive picture of the underlying free energy surfaces and the corresponding dynamics of nucleosome repositioning. The mechanism of nucleosome repositioning is shown to be strongly linked to DNA sequence and directly related to the binding energy of a given DNA sequence to the histone core. It is also demonstrated that chromatin remodelers can override DNA-sequence preferences by exerting torque, and the histone H4 tail is then identified as a key component by which DNA-sequence, histone modifications, and chromatin remodelers could in fact be coupled.

[1]  G. Morin.  The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats , 1989, Cell.

[2]  J J de Pablo,et al.  A mesoscale model of DNA and its renaturation. , 2009, Biophysical journal.

[3]  D M Crothers,et al.  Artificial nucleosome positioning sequences. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[4]  J. Widom,et al.  New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. , 1998, Journal of molecular biology.

[5]  Andrew V. Colasanti,et al.  A novel roll-and-slide mechanism of DNA folding in chromatin: implications for nucleosome positioning. , 2007, Journal of molecular biology.

[6]  L. Nordenskiöld,et al.  ISWI Remodelling of Physiological Chromatin Fibres Acetylated at Lysine 16 of Histone H4 , 2014, PloS one.

[7]  Karolin Luger,et al.  Blocking transcription through a nucleosome with synthetic DNA ligands. , 2002, Journal of molecular biology.

[8]  Taichi E. Takasuka,et al.  Are nucleosome positions in vivo primarily determined by histone–DNA sequence preferences? , 2009, Nucleic acids research.

[9]  M. Zofall,et al.  Chromatin remodeling by ISW2 and SWI/SNF requires DNA translocation inside the nucleosome , 2006, Nature Structural &Molecular Biology.

[10]  S. Takada,et al.  Frustration, specific sequence dependence, and nonlinearity in large-amplitude fluctuations of allosteric proteins , 2011, Proceedings of the National Academy of Sciences.

[11]  Juan J de Pablo,et al.  DNA shape dominates sequence affinity in nucleosome formation. , 2014, Physical review letters.

[12]  G. Narlikar,et al.  The chromatin-remodeling enzyme ACF is an ATP-dependent DNA length sensor that regulates nucleosome spacing , 2006, Nature Structural &Molecular Biology.

[13]  Eric Vanden-Eijnden,et al.  Revisiting the finite temperature string method for the calculation of reaction tubes and free energies. , 2009, The Journal of chemical physics.

[14]  J. Kästner.  Umbrella sampling , 2011 .

[15]  Dustin E. Schones,et al.  Dynamic Regulation of Nucleosome Positioning in the Human Genome , 2008, Cell.

[16]  Juan J de Pablo,et al.  Coarse-grained modeling of DNA curvature. , 2014, The Journal of chemical physics.

[17]  Jonathan Widom,et al.  Dynamics of nucleosome invasion by DNA binding proteins. , 2011, Journal of molecular biology.

[18]  T. Richmond,et al.  The structure of DNA in the nucleosome core , 2003, Nature.

[19]  Irene K. Moore,et al.  A genomic code for nucleosome positioning , 2006, Nature.

[20]  Ryuji Kobayashi,et al.  ACF, an ISWI-Containing and ATP-Utilizing Chromatin Assembly and Remodeling Factor , 1997, Cell.

[21]  C. Bustamante,et al.  Rapid spontaneous accessibility of nucleosomal DNA , 2005, Nature Structural &Molecular Biology.

[22]  Jie Yan,et al.  Nucleosome hopping and sliding kinetics determined from dynamics of single chromatin fibers in Xenopus egg extracts , 2007, Proceedings of the National Academy of Sciences.

[23]  Michelle D. Wang,et al.  High resolution dynamic mapping of histone-DNA interactions in a nucleosome , 2008, Nature Structural &Molecular Biology.

[24]  C. Peterson,et al.  The RSC chromatin remodelling enzyme has a unique role in directing the accurate positioning of nucleosomes , 2011, The EMBO journal.

[25]  Peter C. Kahn,et al.  Defining the axis of a helix , 1989, Comput. Chem..

[26]  E. Bradbury,et al.  Mobility of positioned nucleosomes on 5 S rDNA. , 1991, Journal of molecular biology.

[27]  Steven M. Johnson,et al.  Determinants of nucleosome organization in primary human cells , 2011, Nature.

[28]  J. Widom,et al.  Polymer reptation and nucleosome repositioning. , 2001, Physical review letters.

[29]  T. Richmond,et al.  Mapping nucleosome position at single base-pair resolution by using site-directed hydroxyl radicals. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[30]  J. Knezetic,et al.  The presence of nucleosomes on a DNA template prevents initiation by RNA polymerase II in vitro , 1986, Cell.

[31]  P. Becker,et al.  Nucleosome sliding mechanisms: new twists in a looped history , 2013, Nature Structural &Molecular Biology.

[32]  H. Schiessel,et al.  Nucleosome repositioning via loop formation. , 2002, Biophysical journal.

[33]  E. M. Bradbury,et al.  Mobile nucleosomes‐‐a general behavior. , 1992, The EMBO journal.

[34]  G. Hager,et al.  Transcription factor access is mediated by accurately positioned nucleosomes on the mouse mammary tumor virus promoter , 1991, Molecular and cellular biology.

[35]  R. Kornberg,et al.  Nucleosomes inhibit the initiation of transcription but allow chain elongation with the displacement of histones , 1987, Cell.

[36]  T. Richmond,et al.  Crystal structure of the nucleosome core particle at 2.8 Å resolution , 1997, Nature.

[37]  Andrew J. Spakowitz,et al.  Effect of force on mononucleosomal dynamics , 2006, Proceedings of the National Academy of Sciences.

[38]  K. Rippe,et al.  A 'loop recapture' mechanism for ACF-dependent nucleosome remodeling , 2005, Nature Structural &Molecular Biology.

[39]  T. Richmond,et al.  Positioning and stability of nucleosomes on MMTV 3'LTR sequences. , 1998, Journal of molecular biology.

[40]  Karolin Luger,et al.  Nucleosomes in solution exist as a mixture of twist-defect states. , 2005, Journal of molecular biology.

[41]  Song Tan,et al.  Nucleosome structural studies. , 2011, Current opinion in structural biology.

[42]  Juan J de Pablo,et al.  An experimentally-informed coarse-grained 3-Site-Per-Nucleotide model of DNA: structure, thermodynamics, and dynamics of hybridization. , 2013, The Journal of chemical physics.

[43]  Shankar Kumar,et al.  Multidimensional free‐energy calculations using the weighted histogram analysis method , 1995, J. Comput. Chem..

[44]  A. Shilatifard,et al.  Covalent modifications of histones during development and disease pathogenesis , 2007, Nature Structural &Molecular Biology.

[45]  D. Schwartz,et al.  Tension-Dependent Free Energies of Nucleosome Unwrapping , 2016, ACS central science.

[46]  R. Lavery,et al.  Structure and dynamics of DNA loops on nucleosomes studied with atomistic, microsecond-scale molecular dynamics , 2016, Nucleic acids research.

[47]  Daniel M. Hinckley,et al.  Coarse-Grained Ions for Nucleic Acid Modeling. , 2015, Journal of chemical theory and computation.

[48]  Alexandre V. Morozov,et al.  Using DNA mechanics to predict in vitro nucleosome positions and formation energies , 2009, Nucleic acids research.

[49]  H. Schiessel,et al.  Nucleosome dynamics: Sequence matters. , 2016, Advances in colloid and interface science.

[50]  Eric Vanden-Eijnden,et al.  Simplified and improved string method for computing the minimum energy paths in barrier-crossing events. , 2007, The Journal of chemical physics.

[51]  J. Widom,et al.  Sequence motifs and free energies of selected natural and non-natural nucleosome positioning DNA sequences. , 1999, Journal of molecular biology.

[52]  Oliver J. Rando,et al.  Chromatin remodelling at promoters suppresses antisense transcription , 2007, Nature.

[53]  William L. Hwang,et al.  Histone H4 tail mediates allosteric regulation of nucleosome remodelling by linker DNA , 2014, Nature.

[54]  W. Bickmore,et al.  Human diseases with underlying defects in chromatin structure and modification. , 2001, Human molecular genetics.

[55]  J. Bednar,et al.  Single-base resolution mapping of H1–nucleosome interactions and 3D organization of the nucleosome , 2010, Proceedings of the National Academy of Sciences.

[56]  T. Tsukiyama,et al.  Chromatin remodeling in vivo: evidence for a nucleosome sliding mechanism. , 2003, Molecular cell.

[57]  Irene K. Moore,et al.  The DNA-encoded nucleosome organization of a eukaryotic genome , 2009, Nature.

[58]  T. Richmond,et al.  Solvent mediated interactions in the structure of the nucleosome core particle at 1.9 a resolution. , 2002, Journal of molecular biology.

[59]  G. Bowman.  Mechanisms of ATP-dependent nucleosome sliding. , 2010, Current opinion in structural biology.

[60]  M. Cerone,et al.  In vitro low propensity to form nucleosomes of four telomeric sequences , 1997, FEBS letters.

[61]  K. Luger,et al.  Crystal structures of nucleosome core particles in complex with minor groove DNA-binding ligands. , 2003, Journal of molecular biology.

[62]  K. Struhl,et al.  Intrinsic histone-DNA interactions are not the major determinant of nucleosome positions in vivo , 2009, Nature Structural &Molecular Biology.

[63]  I. Filesi,et al.  The main role of the sequence-dependent DNA elasticity in determining the free energy of nucleosome formation on telomeric DNAs. , 2000, Biophysical chemistry.

[64]  T. Owen-Hughes,et al.  Analysis of Nucleosome Repositioning by Yeast ISWI and Chd1 Chromatin Remodeling Complexes* , 2006, Journal of Biological Chemistry.

[65]  D. Schwartz,et al.  A coarse grain model for DNA. , 2007, The Journal of chemical physics.

[66]  M. L. Dechassa,et al.  Disparity in the DNA translocase domains of SWI/SNF and ISW2 , 2012, Nucleic acids research.

[67]  William L. Hwang,et al.  ISWI Remodelers Slide Nucleosomes with Coordinated Multi-Base-Pair Entry Steps and Single-Base-Pair Exit Steps , 2013, Cell.

[68]  Enrico Marchioni,et al.  Telomeric nucleosomes are intrinsically mobile. , 2007, Journal of molecular biology.

[69]  K. Struhl,et al.  Determinants of nucleosome positioning , 2013, Nature Structural &Molecular Biology.

[70]  L. S. Cram,et al.  A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[71]  R. Kornberg,et al.  Chromatin remodeling by DNA bending, not twisting. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[72]  Yifan Cheng,et al.  The chromatin remodeler ACF acts as a dimeric motor to space nucleosomes , 2009, Nature.

[73]  H. Schiessel,et al.  Chromatin dynamics: nucleosomes go mobile through twist defects. , 2003, Physical review letters.

[74]  P. Becker,et al.  The ATPase domain of ISWI is an autonomous nucleosome remodeling machine , 2012, Nature Structural &Molecular Biology.

[75]  Helmut Schiessel,et al.  Rigid-body molecular dynamics of DNA inside a nucleosome , 2013, The European Physical Journal E.

[76]  Michael D. Stone,et al.  Dynamics of nucleosome remodelling by individual ACF complexes , 2009, Nature.