DNA: At our cores, we're all strengthened by 'dumbbells'

Date:
October 21, 2020
Source:
Rice University
Summary:
Scientists detail the structure of dumbbell-like sequences in DNA
during interphase that suggest several unseen aspects of chromosome
configuration and function.



FULL STORY ==========================================================================
How life works may come down to dumbbell-like bits of DNA.


==========================================================================
Rice University scientists on a long quest to study the structure and
function of chromosomes have found that amid the apparent chaotic state
of DNA during interphase, when cells are between divisions, there are
pockets of order in the configuration of certain gene-containing regions.

These structures, reported in an open-access eLife study, offer a window
into how chromosomes function and promise new avenues of research for
those digging into their secrets.

The work led by Rice postdoctoral fellow and lead author Ryan Cheng
and principal investigator Jose' Onuchic, co-director of the Rice-based
Center for Theoretical Biological Physics (CTBP), employs sophisticated simulations and evidence from experiments to suggest several new aspects
of chromosome configuration and function.

"In molecular biology and gene expression, people talk about transcription factors and inhibitors and enhancers, but it seems there is no structural information," Onuchic said. "With advances in looking at chromatin
structures, it starts to become possible to know how these structures
and chromatin dynamics control gene expression.

"This paper suggests, for the first time, a mechanism connecting genome structure and gene expression," he said.



==========================================================================
The researchers lay out four results from their coarse-grained Minimal Chromatin Model (MiChroM), a technique drawn from 20 years of experience
with their energy landscape theory for predicting the structure of
proteins.

First, they used MiChroM to predict chromosome structural ensembles
for different cell types using the associated epigenetic markers as the
sole input, finding the predictions to be consistent with experimental observations.

In previous research, they used MiChroM to simulate individual chromosomes
in lymphoblastoid cells. The new work implies that the principles they discovered in that work also apply generally to different human cell
types, highlighting the transferability of their theoretical model.

Second, with data from experiments using 3D tracing, which helps
to directly visualize the tangle of DNA in a cell's nucleus during
interphase, they determined the structures of chromosomes are all
different. Yet they also found distinct clusters with what appear to
be common structures, genes that have flexible, dumbbell-like globular
domains at the head and the tail.

Cheng said their analysis of the experimental images revealed three
distinct clusters among the disorder. "We believe that one is an artifact,
but in the other two, the structures are either closed, meaning the two globular domains at the head and the tail are more or less touching, or
open, where the domains have come apart," he said. This same structural transition appeared in the group's simulations using MiChroM.



========================================================================== Third, the researchers found that genes contained in this dumbbell
structure are all located within the string that links the globular
ends. "The fact that we find these structures undergo an open-close
transition plausibly suggests it's related to transcriptional regulation," Cheng said. "This is suggestive of a direct relationship between
the structure and functional aspects of gene expression." Finally,
the section of chromosome 21 detailed via experiments and modeled at
Rice showed the position of the "dumbbells" is dynamic, with "A-type" structures moving to the surface of the disordered chromosome when they
are functionally active, while inactive or "B-type" structures tend to
move to the interior.

What drives active chromatin to the surface requires further study,
Onuchic said.

"Maybe genes that have to be expressed, for example in early development,
are activated and then move to the core of the chromosome because they're
not used again," he said. "But that remains to be proven. We have just
started to show evidence in that regard." "No one should be under
the illusion that a program of research by five or six scientists can
by itself ultimately answer all the questions about gene regulation,"
said co-author Peter Wolynes, co-director of the CTBP. "The same was
true when we began to study protein folding. What was necessary there
was to get to create new ways of thinking about the problem and make predictions that inspired experimentalists.

"In the same way, we now have to educate experimentalists in this new
way of thinking about how chromosomes act," he said.


========================================================================== Story Source: Materials provided by Rice_University. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Ryan R Cheng, Vinicius Contessoto, Erez Lieberman-Aiden, Peter
G Wolynes,
Michele Di Pierro, Jose N Onuchic. Exploring chromosomal structural
heterogeneity across multiple cell lines. eLife, 2020; 9 DOI:
10.7554/ eLife.60312 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/10/201021140912.htm

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