• Structures considered key to gene expres

    From ScienceDaily@1:317/3 to All on Thu Apr 14 22:30:46 2022
    Structures considered key to gene expression are surprisingly fleeting


    Date:
    April 14, 2022
    Source:
    Massachusetts Institute of Technology
    Summary:
    Scientists find that loops in the genome may be much rarer and
    shorter- lived than previously thought, lasting only tens of
    minutes, which suggests current theories of how loops influence
    gene expression may need to be revised.



    FULL STORY ==========================================================================
    In human chromosomes, DNA is coated by proteins to form an exceedingly
    long beaded string. This "string" is folded into numerous loops, which
    are believed to help cells control gene expression and facilitate DNA
    repair, among other functions. A new study from MIT suggests that these
    loops are very dynamic and shorter-lived than previously thought.


    ==========================================================================
    In the new study, the researchers were able to monitor the movement of
    one stretch of the genome in a living cell for about two hours. They saw
    that this stretch was fully looped for only 3 to 6 percent of the time,
    with the loop lasting for only about 10 to 30 minutes. The findings
    suggest that scientists' current understanding of how loops influence
    gene expression may need to be revised, the researchers say.

    "Many models in the field have been these pictures of static loops
    regulating these processes. What our new paper shows is that this picture
    is not really correct," says Anders Sejr Hansen, the Underwood-Prescott
    Career Development Assistant Professor of Biological Engineering at
    MIT. "We suggest that the functional state of these domains is much
    more dynamic." Hansen is one of the senior authors of the new study,
    along with Leonid Mirny, a professor in MIT's Institute for Medical
    Engineering and Science and the Department of Physics, and Christoph
    Zechner, a group leader at the Max Planck Institute of Molecular Cell
    Biology and Genetics in Dresden, Germany, and the Center for Systems
    Biology Dresden. MIT postdoc Michele Gabriele, recent Harvard University
    PhD recipient Hugo Branda~o, and MIT graduate student Simon Grosse-Holz
    are the lead authors of the paper, which appears today in Science.

    Out of the loop Using computer simulations and experimental data,
    scientists including Mirny's group at MIT have shown that loops in the
    genome are formed by a process called extrusion, in which a molecular
    motor promotes the growth of progressively larger loops. The motor stops
    each time it encounters a "stop sign" on DNA. The motor that extrudes such loops is a protein complex called cohesin, while the DNA-bound protein
    CTCF serves as the stop sign. These cohesin-mediated loops between CTCF
    sites were seen in previous experiments.



    ========================================================================== However, those experiments only offered a snapshot of a moment in time,
    with no information on how the loops change over time. In their new study,
    the researchers developed techniques that allowed them to fluorescently
    label CTCF DNA sites so they could image the DNA loops over several
    hours. They also created a new computational method that can infer the
    looping events from the imaging data.

    "This method was crucial for us to distinguish signal from noise in
    our experimental data and quantify looping," Zechner says. "We believe
    that such approaches will become increasingly important for biology
    as we continue to push the limits of detection with experiments."
    The researchers used their method to image a stretch of the genome in
    mouse embryonic stem cells. "If we put our data in the context of one
    cell division cycle, which lasts about 12 hours, the fully formed loop
    only actually exists for about 20 to 45 minutes, or about 3 to 6 percent
    of the time," Grosse-Holz says.

    "If the loop is only present for such a tiny period of the cell cycle
    and very short-lived, we shouldn't think of this fully looped state as
    being the primary regulator of gene expression," Hansen says. "We think
    we need new models for how the 3D structure of the genome regulates
    gene expression, DNA repair, and other functional downstream processes."
    While fully formed loops were rare, the researchers found that partially extruded loops were present about 92 percent of the time. These smaller
    loops have been difficult to observe with the previous methods of
    detecting loops in the genome.



    ==========================================================================
    "In this study, by integrating our experimental data with polymer
    simulations, we have now been able to quantify the relative extents of
    the unlooped, partially extruded, and fully looped states," Branda~o says.

    "Since these interactions are very short, but very frequent, the
    previous methodologies were not able to fully capture their dynamics,"
    Gabriele adds.

    "With our new technique, we can start to resolve transitions between
    fully looped and unlooped states." The researchers hypothesize that
    these partial loops may play more important roles in gene regulation than
    fully formed loops. Strands of DNA run along each other as loops begin
    to form and then fall apart, and these interactions may help regulatory elements such as enhancers and gene promoters find each other.

    "More than 90 percent of the time, there are some transient loops,
    and presumably what's important is having those loops that are being perpetually extruded," Mirny says. "The process of extrusion itself
    may be more important than the fully looped state that only occurs for
    a short period of time." More loops to study Since most of the other
    loops in the genome are weaker than the one the researchers studied in
    this paper, they suspect that many other loops will also prove to be
    highly transient. They now plan to use their new technique study some
    of those other loops, in a variety of cell types.

    "There are about 10,000 of these loops, and we've looked at one,"
    Hansen says.

    "We have a lot of indirect evidence to suggest that the results
    would be generalizable, but we haven't demonstrated that. Using the
    technology platform we've set up, which combines new experimental and computational methods, we can begin to approach other loops in the
    genome." The researchers also plan to investigate the role of specific
    loops in disease.

    Many diseases, including a neurodevelopmental disorder called FOXG1
    syndrome, could be linked to faulty loop dynamics. The researchers are now studying how both the normal and mutated form of the FOXG1 gene, as well
    as the cancer- causing gene MYC, are affected by genome loop formation.

    The research was funded by the National Institutes of Health, the National Science Foundation, the Mathers Foundation, a Pew-Stewart Cancer Research Scholar grant, the Chaires d'excellence Internationale Blaise Pascal,
    an American-Italian Cancer Foundation research scholarship, and the Max
    Planck Institute for Molecular Cell Biology and Genetics.


    ========================================================================== Story Source: Materials provided by
    Massachusetts_Institute_of_Technology. Original written by Anne
    Trafton. Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Michele Gabriele, Hugo B. Branda~o, Simon Grosse-Holz, Asmita
    Jha, Gina
    M. Dailey, Claudia Cattoglio, Tsung-Han S. Hsieh, Leonid
    Mirny, Christoph Zechner, Anders S. Hansen. Dynamics of CTCF-
    and cohesin-mediated chromatin looping revealed by live-cell
    imaging. Science, 2022; DOI: 10.1126/science.abn6583 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220414143929.htm

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