Systems Biology Approaches for Understanding Genome Architecture.

The linear and three-dimensional arrangement and composition of chromatin in eukaryotic genomes underlies the mechanisms directing gene regulation. Understanding this organization requires the integration of many data types and experimental results. Here we describe the approach of integrating genome-wide protein-DNA binding data to determine chromatin states. To investigate spatial aspects of genome organization, we present a detailed description of how to run stochastic simulations of protein movements within a simulated nucleus in 3D. This systems level approach enables the development of novel questions aimed at understanding the basic mechanisms that regulate genome dynamics.

[1]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[2]  D. Bray,et al.  Simulated Diffusion of Phosphorylated CheY through the Cytoplasm of Escherichia coli , 2005, Journal of bacteriology.

[3]  P. Flicek,et al.  The Ensembl Regulatory Build , 2015, Genome Biology.

[4]  A. Verkman,et al.  Translational Diffusion of Macromolecule-sized Solutes in Cytoplasm and Nucleus , 1997, The Journal of cell biology.

[5]  Jennifer A. Mitchell,et al.  Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells , 2010, Nature Genetics.

[6]  Tadashi Ando,et al.  Sliding of Proteins Non-specifically Bound to DNA: Brownian Dynamics Studies with Coarse-Grained Protein and DNA Models , 2014, PLoS Comput. Biol..

[7]  P. V. von Hippel,et al.  Diffusion-driven mechanisms of protein translocation on nucleic acids. 1. Models and theory. , 1981, Biochemistry.

[8]  Manolis Kellis,et al.  Large-scale epigenome imputation improves data quality and disease variant enrichment , 2015, Nature Biotechnology.

[9]  S. Andrews,et al.  An Integrated Model of Transcription Factor Diffusion Shows the Importance of Intersegmental Transfer and Quaternary Protein Structure for Target Site Finding , 2014, PloS one.

[10]  M. Daly,et al.  Genetic and Epigenetic Fine-Mapping of Causal Autoimmune Disease Variants , 2014, Nature.

[11]  A. Kolomeisky,et al.  Speed-selectivity paradox in the protein search for targets on DNA: is it real or not? , 2013, The journal of physical chemistry. B.

[12]  B. Steensel,et al.  Chromatin organization: form to function. , 2013 .

[13]  L. Baum,et al.  An inequality and associated maximization technique in statistical estimation of probabilistic functions of a Markov process , 1972 .

[14]  Achilleas S Frangakis,et al.  Human mitotic chromosomes consist predominantly of irregularly folded nucleosome fibres without a 30‐nm chromatin structure , 2012, The EMBO journal.

[15]  Gordon K Smyth,et al.  Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments , 2004, Statistical applications in genetics and molecular biology.

[16]  Paz Polak,et al.  Cell-of-origin chromatin organization shapes the mutational landscape of cancer , 2015, Nature.

[17]  L. Mirny,et al.  Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data , 2013, Nature Reviews Genetics.

[18]  Manolis Kellis,et al.  Discovery and Characterization of Chromatin States for Systematic Annotation of the Human Genome , 2011, RECOMB.

[19]  Karen Lipkow,et al.  Simulating the Bacterial Chemotaxis Pathway at High Spatio-temporal Detail , 2014 .

[20]  Gos Micklem,et al.  Supporting Online Material Materials and Methods Figs. S1 to S50 Tables S1 to S18 References Identification of Functional Elements and Regulatory Circuits by Drosophila Modencode , 2022 .

[21]  P. V. von Hippel,et al.  Diffusion-controlled macromolecular interactions. , 1985, Annual review of biophysics and biophysical chemistry.

[22]  Rachel Patton McCord,et al.  Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome , 2013, Genome research.

[23]  David F. Meaney,et al.  Computational Investigation of the Changing Patterns of Subtype Specific NMDA Receptor Activation during Physiological Glutamatergic Neurotransmission , 2011, PLoS Comput. Biol..

[24]  Van Nostrand,et al.  Error Bounds for Convolutional Codes and an Asymptotically Optimum Decoding Algorithm , 1967 .

[25]  Karen Lipkow,et al.  Introducing simulated cellular architecture to the quantitative analysis of fluorescent microscopy. , 2009, Progress in biophysics and molecular biology.

[26]  Tom Misteli,et al.  Functional implications of genome topology , 2013, Nature Structural &Molecular Biology.

[27]  Timothy J. Durham,et al.  "Systematic" , 1966, Comput. J..

[28]  Radek Erban,et al.  Multiscale reaction-diffusion simulations with Smoldyn , 2015, Bioinform..

[29]  B. Cairns.  The logic of chromatin architecture and remodelling at promoters , 2009, Nature.

[30]  Roger Brent,et al.  Detailed Simulations of Cell Biology with Smoldyn 2.1 , 2010, PLoS Comput. Biol..

[31]  D. Bray,et al.  Stochastic simulation of chemical reactions with spatial resolution and single molecule detail , 2004, Physical biology.

[32]  J. Dekker,et al.  The long-range interaction landscape of gene promoters , 2012, Nature.

[33]  István Miklós,et al.  A linear memory algorithm for Baum-Welch training , 2005, BMC Bioinformatics.

[34]  J. Elf,et al.  Probing Transcription Factor Dynamics at the Single-Molecule Level in a Living Cell , 2007, Science.

[35]  Lovelace J. Luquette,et al.  Comprehensive analysis of the chromatin landscape in Drosophila , 2010, Nature.

[36]  Jennifer E. Phillips-Cremins,et al.  Architectural Protein Subclasses Shape 3D Organization of Genomes during Lineage Commitment , 2013, Cell.

[37]  S. Halford,et al.  Protein motion from non‐specific to specific DNA by three‐dimensional routes aided by supercoiling , 2003, The EMBO journal.

[38]  Timothy J. Durham,et al.  Combinatorial Patterning of Chromatin Regulators Uncovered by Genome-wide Location Analysis in Human Cells , 2011, Cell.

[39]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[40]  Samuel A. Isaacson,et al.  The Influence of Spatial Variation in Chromatin Density Determined by X-Ray Tomograms on the Time to Find DNA Binding Sites , 2013, Bulletin of mathematical biology.

[41]  J. Langowski,et al.  Mapping eGFP Oligomer Mobility in Living Cell Nuclei , 2009, PloS one.

[42]  S. Halford,et al.  Measurement of the contributions of 1D and 3D pathways to the translocation of a protein along DNA. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Max Hoffmann,et al.  Oscillations of Min-proteins in micropatterned environments: a three-dimensional particle-based stochastic simulation approach. , 2014, Soft matter.

[44]  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.

[45]  Guo-Cheng Yuan,et al.  Chromatin States Accurately Classify Cell Differentiation Stages , 2012, PloS one.

[46]  Ieuan Clay,et al.  The transcriptional interactome: gene expression in 3D. , 2010, Current opinion in genetics & development.

[47]  Eder Zavala,et al.  The Long and Viscous Road: Uncovering Nuclear Diffusion Barriers in Closed Mitosis , 2014, PLoS Comput. Biol..

[48]  Guillaume J. Filion,et al.  Systematic Protein Location Mapping Reveals Five Principal Chromatin Types in Drosophila Cells , 2010, Cell.

[49]  Steven S Andrews,et al.  Spatial and stochastic cellular modeling with the Smoldyn simulator. , 2012, Methods in molecular biology.