title: Training-free atomistic prediction of nucleosome occupancy.
abstract: Nucleosomes alter gene expression by preventing transcription factors from occupying binding sites along DNA. DNA methylation can affect nucleosome positioning and so alter gene expression epigenetically (without changing DNA sequence). Conventional methods to predict nucleosome occupancy are trained on observed DNA sequence patterns or known DNA oligonucleotide structures. They are statistical and lack the physics needed to predict subtle epigenetic changes due to DNA methylation. The training-free method presented here uses physical principles and state-of-the-art all-atom force fields to predict both nucleosome occupancy along genomic sequences as well as binding to known positioning sequences. Our method calculates the energy of both nucleosomal and linear DNA of the given sequence. Based on the DNA deformation energy, we accurately predict the in vitro occupancy profile observed experimentally for a 20,000-bp genomic region as well as the experimental locations of nucleosomes along 13 well-established positioning sequence elements. DNA with all C bases methylated at the 5 position shows less variation of nucleosome binding: Strong binding is weakened and weak binding is strengthened compared with normal DNA. Methylation also alters the preference of nucleosomes for some positioning sequences but not others.
authors.affiliation: Department of Computer Science, University of Oxford, Oxford OX1 3QD, United Kingdom.
authors.forename: Peter
authors.initials: P
authors.lastname: Minary
authors.forename: Michael
authors.initials: M
authors.lastname: Levitt
mesh_terms: D001482:Base Composition / Q000235:genetics; D001483:Base Sequence; D019175:DNA Methylation / Q000235:genetics; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009707:Nucleosomes / Q000737:chemistry / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D013698:Templates, Genetic; D013816:Thermodynamics; D014158:Transcription, Genetic
chemical_list: D004271:DNA, Fungal; D009707:Nucleosomes
keywords: large-scale optimization; sequence threading; transcriptional regulation
references.citation: Nat Rev Genet. 2009 May;10(5):295-304
references.pmid: 19308066
references.citation: Proc Natl Acad Sci U S A. 1980 Jul;77(7):3816-20
references.pmid: 6933438
references.citation: Nucleic Acids Res. 1998 Jan 1;26(1):73-9
references.pmid: 9399804
references.citation: Proc Natl Acad Sci U S A. 1978 Feb;75(2):640-4
references.pmid: 273227
references.citation: Oncogene. 2012 Mar 29;31(13):1609-22
references.pmid: 21860412
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references.pmid: 10592235
references.citation: Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1370-5
references.pmid: 8643638
references.citation: Science. 2005 Jul 22;309(5734):626-30
references.pmid: 15961632
references.citation: Curr Opin Genet Dev. 2011 Apr;21(2):175-86
references.pmid: 21342762
references.citation: J Comput Biol. 2010 Aug;17(8):993-1010
references.pmid: 20726792
references.citation: Nucleic Acids Res. 2011 Sep 1;39(16):6956-69
references.pmid: 21622955
references.citation: J Mol Biol. 2002 Jun 21;319(5):1097-113
references.pmid: 12079350
references.citation: Nature. 2003 May 8;423(6936):145-50
references.pmid: 12736678
references.citation: Nature. 2010 Jul 15;466(7304):388-92
references.pmid: 20512117
references.citation: J Biomol Struct Dyn. 2010 Jun;27(6):821-41
references.pmid: 20232936
references.citation: BMC Bioinformatics. 2009 Dec 22;10:442
references.pmid: 20028554
references.citation: Cancer Cell. 2002 May;1(4):299-305
references.pmid: 12086841
references.citation: J Mol Biol. 1986 Oct 20;191(4):659-75
references.pmid: 3806678
references.citation: Nat Struct Mol Biol. 2007 Nov;14(11):989-96
references.pmid: 17984961
references.citation: Nucleic Acids Res. 2011 Nov 1;39(20):8740-51
references.pmid: 21775342
references.citation: Biophys J. 2007 Jun 1;92(11):3817-29
references.pmid: 17351000
references.citation: Biochemistry. 1988 Apr 19;27(8):2970-8
references.pmid: 2840954
references.citation: Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S4-11
references.pmid: 16341240
references.citation: Structure. 2005 Oct;13(10):1499-509
references.pmid: 16216581
references.citation: Phys Chem Chem Phys. 2009 Dec 7;11(45):10712-21
references.pmid: 20145815
references.citation: Cell. 2007 Feb 23;128(4):635-8
references.pmid: 17320500
references.citation: Nucleic Acids Res. 2005 Nov 27;33(20):e176
references.pmid: 16314307
references.citation: Nature. 2009 Mar 19;458(7236):362-6
references.pmid: 19092803
references.citation: PLoS One. 2010 Sep 01;5(9):
references.pmid: 20824131
references.citation: J Biomol Struct Dyn. 2010 Jun;27(6):725-39
references.pmid: 20232929
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11163-8
references.pmid: 9736707
references.citation: Nature. 2012 Jun 28;486(7404):496-501
references.pmid: 22722846
references.citation: Nucleic Acids Res. 1981 Jun 25;9(12):2659-73
references.pmid: 6269057
references.citation: Science. 1974 May 24;184(4139):868-71
references.pmid: 4825889
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):E2514-22
references.pmid: 22908247