title: The Global Relationship between Chromatin Physical Topology, Fractal Structure, and Gene Expression.
abstract: Most of what we know about gene transcription comes from the view of cells as molecular machines: focusing on the role of molecular modifications to the proteins carrying out transcriptional reactions at a loci-by-loci basis. This view ignores a critical reality: biological reactions do not happen in an empty space, but in a highly complex, interrelated, and dense nanoenvironment that profoundly influences chemical interactions. We explored the relationship between the physical nanoenvironment of chromatin and gene transcription in vitro. We analytically show that changes in the fractal dimension, D, of chromatin correspond to simultaneous increases in chromatin accessibility and compaction heterogeneity. Using these predictions, we demonstrate experimentally that nanoscopic changes to chromatin D within thirty minutes correlate with concomitant enhancement and suppression of transcription. Further, we show that the increased heterogeneity of physical structure of chromatin due to increase in fractal dimension correlates with increased heterogeneity of gene networks. These findings indicate that the higher order folding of chromatin topology may act as a molecular-pathway independent code regulating global patterns of gene expression. Since physical organization of chromatin is frequently altered in oncogenesis, this work provides evidence pairing molecular function to physical structure for processes frequently altered during tumorigenesis.
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Almassalha
authors.affiliation: Section of Gastroenterology, Boston Medical Center/Boston University School of Medicine, Boston, Massachusetts, 02118, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
authors.forename: P T
authors.initials: PT
authors.lastname: Ruhoff
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Stypula-Cyrus
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cherkezyan
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: H
authors.initials: H
authors.lastname: Matsuda
authors.affiliation: Section of Gastroenterology, Boston Medical Center/Boston University School of Medicine, Boston, Massachusetts, 02118, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Dela Cruz
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Chandler
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: C
authors.initials: C
authors.lastname: White
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: C
authors.initials: C
authors.lastname: Maneval
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: H
authors.initials: H
authors.lastname: Subramanian
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.|Department of Chemistry, Northwestern University, Evanston, Illinois, 60208, USA.|Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: I
authors.initials: I
authors.lastname: Szleifer
authors.affiliation: Section of Gastroenterology, Boston Medical Center/Boston University School of Medicine, Boston, Massachusetts, 02118, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Roy
authors.affiliation: Department of Biomedical Engineering, Northwestern University, Evanston, Illinois, 60208, USA.|Chemistry of Life Processes Institute, Northwestern University, Evanston, Illinois, 60208, USA.
authors.forename: V
authors.initials: V
authors.lastname: Backman
mesh_terms: D002843:Chromatin / Q000378:metabolism*; D017709:Fractals; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D019073:HT29 Cells; D006801:Humans; D008954:Models, Biological; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin