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.

Macrogenomic engineering via modulation of the scaling of chromatin packing density

“…As shown by equation (5), the influence of the change in the packing-density scaling of chromatin on gene expression depends on: (1) the average initial (that is, preceding the perturbation) expression rate $\overline{\epsilon }$ determined by m , (2) the initial D , (3) the upper length-scale of packing-density scaling of chromatin $\left(\frac{M_f}{M_{min}}\right)$, (4) gene length L , and (5) the size of the interaction volume (see Supplementary Section 1 for the derivation). These parameters were obtained experimentally and from the simulations: initial gene expression and D for each condition were obtained by microarray and PWS microscopy measurements respectively 11,44 , $\frac{M_f}{M_{min}}$ was assumed to correspond to the average size of a single chromosome, L was calculated as the average gene length for genes in the microarray data set, and the radius of the interaction volume was determined from the depletion distance between DNA and transcription factors from simulations (Supplementary equation (7)) 13,45 .…”

Quantifying Three-dimensional Chromatin Organization Utilizing Scanning Transmission Electron Microscopy: ChromSTEM

“…ChromSTEM platform for analysis of chromatin organization 3D chromatin organization governs gene transcription by controlling genome connectivity, DNA accessibility, and transcriptional heterogeneity 26,27,28 . Emerging evidence shows that the proper positioning of the chromatin within the nucleus also plays an indispensable role in maintaining normal transcriptional function 10,29 .…”

Multimodal interferometric imaging of nanoscale structure and macromolecular motion uncovers UV induced cellular paroxysm

“…Similarly, this interference signal will vary in time, referred to in this paper as temporal interference, depending on the motion of those intracellular structures. can be found in previous works 10,[19][20][21][22][23] .…”

“…This interference produces spectral variations that depend on the nanoscale organization of these structures. PWS has resulted in many breakthroughs in the study of the higher-order organization of chromatin structure, its relation to the development of cancer 7,11 , and its use in cancer diagnostics [12][13][14][15][16][17] and therapeutics 18 . The same interference phenomenon that enables PWS to probe intracellular structure at length-scales below the diffraction limit without the use of labels can be utilized to retrieve information on macromolecular motion by measuring temporal variations in the interference signal instead of spatial (wavelength) variations.…”