Developmental biology - Genes|
How Dancing DNA Might Express Genes
New simulations reveal DNA flows across a cell's nucleus in a choreographed line dance...
New simulations reveal DNA flows across a cell's nucleus in a choreographed line dance, the first large-scale explanation for how genetic material moves within a working cell.
"Previous work focused on what was going on at the microscale of DNA. People didn't really think about what was going on at a larger scale." says study co-author Michael Shelley, group leader for biophysical modeling at the Flatiron Institute's Center for Computational Biology in New York City and co-director of the Courant Institute's Applied Mathematics Laboratory at New York University.
Shelley and colleagues computer simulated the motion of chromatin, the functional form of DNA inside a nucleus. Chromatin looks like a string of beads, with ball-like clusters of genes linked on DNA strands. The researchers propose that molecular machines move along the strands of DNA causing segments of chromatin to straighten and pull taut. This motion aligns neighboring strands to face in the same direction. That alignment results in a cascading waltz of genetic material shimmying across the nucleus.
Dancing DNA may play a role in gene expression, replication and remodeling, though the exact effects of this are still being examined. The researchers reported their results online October 22 in Proceedings of the National Academy of Sciences or PNAS.
Their findings help explain measurements reported in 2013 by Alexandra Zidovska of Harvard University who identified small-scale motion of individual genes. Zidovska's experiments revealed large regions of chromatin shifting in unison throughout a cell nucleus, at a rate of a fraction of a micron every few seconds. Although capturing this movement, he did not identify the mechanical details involved.
However, Shelley had experience studying microbial swimming. The similar physics involved made him curious about mechanisms behind these gyrating DNA strands. He partnered with David Saintillan of the University of California, San Diego, and Zidovska, now of New York University, to investigate these movements more thoroughly. Together the team observed two ways molecular machines might move along a DNA molecule pulling and pushing nearby genetic material.
Molecular machines can't exert net force. While pulling on one length of DNA, a molecular machine must hold or pull another DNA strand — cancelling out the first force and contracting the DNA segment. If instead the molecular machine pushes outward on a DNA strand, this will similarly create another outward force, and extend the DNA strand.
Using computer simulations, the team modeled how repeated contractions and extensions of DNA affect the compacted chromatin inside a nucleus. DNA contractions moving strands in one direction; extensions pushing DNA outwardly in another direction, create a flow of shifting patches of DNA and the genetic material attached.
Shelley proposes this DNA shimmy could be responsible for allowing the expression of particular genes. But creating an exact model for gene expression (function) will require more complex computer simulations into how well chromatin "dances" its way across the nucleus.
The 3D spatiotemporal organization of the human genome inside the cell nucleus remains a major open question in cellular biology. In the time between two cell divisions, chromatin—the functional form of DNA in cells—fills the nucleus in its uncondensed polymeric form. Recent in vivo imaging experiments reveal that the chromatin moves coherently, having displacements with long-ranged correlations on the scale of micrometers and lasting for seconds. To elucidate the mechanism(s) behind these motions, we develop a coarse-grained active polymer model where chromatin is represented as a confined flexible chain acted upon by molecular motors that drive fluid flows by exerting dipolar forces on the system. Numerical simulations of this model account for steric and hydrodynamic interactions as well as internal chain mechanics. These demonstrate that coherent motions emerge in systems involving extensile dipoles and are accompanied by large-scale chain reconfigurations and nematic ordering. Comparisons with experiments show good qualitative agreement and support the hypothesis that self-organizing long-ranged hydrodynamic couplings between chromatin-associated active motor proteins are responsible for the observed coherent dynamics.
While the sequence of the human genome has been known for two decades, its 3D dynamic organization inside the cell nucleus has remained elusive. Experiments by displacement correlation spectroscopy (DCS) reveal the existence of slow coherent chromatin motions occurring on micrometer-second scales, which are ATP-dependent but have yet to be explained. Using a coarse-grained computational model for the chromatin as a flexible polymer chain acted upon by active force dipoles representing the action of ATP-powered enzymes, we explore the microscopic mechanisms for the emergence of coherent dynamics via hydrodynamic interactions. Extensile dipolar activity is found to drive large-scale chain motions akin to experimental observations through microstructural reconfigurations of the chromatin chain by long-ranged nucleoplasmic flows.
David Saintillan, Michael J. Shelley, and Alexandra Zidovska.
The Flatiron Institute is the research division of the Simons Foundation. The institute's mission is to advance scientific research through computational methods, including data analysis, modeling and simulation. The institute's Center for Computational Biology develops new and innovative methods of examining data in the biological sciences whose scale and complexity have historically resisted analysis. The center's mission is to develop modeling tools and theory for understanding biological processes and to create computational frameworks that will enable the analysis of the large, complex data sets being generated by new experimental technologies.
Return to top of page
Oct 31, 2018 Fetal Timeline Maternal Timeline News News Archive
Computer simulation of a tangled ball of chromatin in a spherical nucleus.
illustrating this image. Credit: Saintillan, Shelley and Zidovska/PNAS 2018