Understanding chromosome organization and its control of gene expression represents one of the most fundamental and significant open biological challenges. Modeling the folding states of chromatin on various spatial and temporal scales is key for unraveling the most basic cellular functions, including transcription activation, gene silencing, and epigenetic control. In this proposal, we continue our innovative modeling project on chromatin modeling started in 2000 that has provided novel and high-impact publications concerning chromatin organization and dynamics to incorporate new factors that expand the model scope and impact significant biological problems. We also add an experimental collaborator, Dr. Sergei Grigoryev, with whom we have already worked successfully, [and a team at Stanford's Simbios National Center for Biomedical Computation, to help disseminate our software tools and enhance our project's impact.] Our long term goal is to integrate structural and dynamical aspects of chromatin organization to delineate the thermodynamic mechanisms of transcriptional regulation mediated through protein factors, epigenetic marks, and environmental conditions. To advance in this goal, we will study:
(Aim 1) chromatin structure and folding with multivalent ions and dynamic ionic distribution;
(Aim 2) chromatin secondary structure folding under different internal and external factors;
(Aim 3) tertiary chromatin organization with divalent ions, chromatin fiber concentration, and architectural proteins.
In Aim 1, we will develop a rigorous model of chromatin folding with multivalent ions by using a combination of Poisson-Boltzmann theory, an improved representation of screening potential functions, and a method for computing screening potentials as the chromatin conformation changes.
In Aim 2, we will explore the effects in the structure of the 30-nm chromatin fiber of DNA linker length variability, histone variants, epigenetic modifications and external forces [using an innovative combination of mesoscale, multiresolution and all-atom models.] In Aim 3, we will model tertiary chromatin structures induced by multivalent ions, concentrated fiber environments, and bound proteins to unravel the structural mechanisms for fiber-fiber interactions and fiber-loop formation and advance our understanding of transcriptional control via large-scale alterations of chromatin folds. These challenging studies in delineating chromatin organization, energetic, and dynamics examined with innovative modeling and experimental techniques, will help elucidate key structure/function connections that fundamentally regulate genomic organization and expression. The experimental collaboration with Dr. Grigoryev will help integrate experiment and theory;[the collaboration with Dr. R. Altman at Stanford's Simbios will help disseminate our developed tools and enhance project impact.] The developed models and methods are applicable to other complex macromolecules systems. Ultimately, this work's results have practical applications by impacting design of agents that control nucleosome composition and chromatin folds.
Chromatin organization affects the most basic and significant cellular functions including transcription regulation and epigenetic control. Our project will elucidate the structural mechanisms of chromatin organization by modeling the folding states of chromatin on various spatial and temporal scales using innovative modeling and simulation tools. Understanding these mechanisms is important for interpreting normal and aberrant states of cellular function and designing agents that affect these processes for biomedical applications.
|Luque, Antoni; Ozer, Gungor; Schlick, Tamar (2016) Correlation among DNA Linker Length, Linker Histone Concentration, and Histone Tails in Chromatin. Biophys J 110:2309-2319|
|Grigoryev, Sergei A; Bascom, Gavin; Buckwalter, Jenna M et al. (2016) Hierarchical looping of zigzag nucleosome chains in metaphase chromosomes. Proc Natl Acad Sci U S A 113:1238-43|
|Collepardo-Guevara, Rosana; Portella, Guillem; Vendruscolo, Michele et al. (2015) Chromatin Unfolding by Epigenetic Modifications Explained by Dramatic Impairment of Internucleosome Interactions: A Multiscale Computational Study. J Am Chem Soc 137:10205-15|
|Ozer, Gungor; Collepardo-Guevara, Rosana; Schlick, Tamar (2015) Forced unraveling of chromatin fibers with nonuniform linker DNA lengths. J Phys Condens Matter 27:064113|
|Ozer, Gungor; Luque, Antoni; Schlick, Tamar (2015) The chromatin fiber: multiscale problems and approaches. Curr Opin Struct Biol 31:124-39|
|Luque, Antoni; Collepardo-Guevara, Rosana; Grigoryev, Sergei et al. (2014) Dynamic condensation of linker histone C-terminal domain regulates chromatin structure. Nucleic Acids Res 42:7553-60|
|Collepardo-Guevara, Rosana; Schlick, Tamar (2014) Chromatin fiber polymorphism triggered by variations of DNA linker lengths. Proc Natl Acad Sci U S A 111:8061-6|
|Collepardo-Guevara, Rosana; Schlick, Tamar (2013) Insights into chromatin fibre structure by inýývitro and in silico single-molecule stretching experiments. Biochem Soc Trans 41:494-500|
|Schlick, Tamar; Hayes, Jeff; Grigoryev, Sergei (2012) Toward convergence of experimental studies and theoretical modeling of the chromatin fiber. J Biol Chem 287:5183-91|
|Collepardo-Guevara, Rosana; Schlick, Tamar (2012) Crucial role of dynamic linker histone binding and divalent ions for DNA accessibility and gene regulation revealed by mesoscale modeling of oligonucleosomes. Nucleic Acids Res 40:8803-17|
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