Scientists pinpoint protein's role in critical gene expression

Date:
December 2, 2021
Source:
University of North Carolina Health Care
Summary:
New research has implications for cancer research because it
explains part of the paradox for how cells can transcribe genes
in the absence of high-energy sources, a situation that unfolds
in cancer and has puzzled researchers for years.



FULL STORY ==========================================================================
Each cell in our body needs a fuel source to grow and divide to keep
us alive.

Most cells prefer a fuel source of high energy-containing sugar, but
there are many times when our cells find themselves in short supply and
must find other sources of energy to maintain their basic functions to
stay alive. As most organisms experience times of feast and famine,
cells have evolved ways to respond rapidly to a changing nutrient
environment. The lab of Brian Strahl, PhD, interim chair of the UNC
Department of Biochemistry and Biophysics at the UNC School of Medicine
has unraveled more details for how cells do this, garnering insights
into the basic ways in which cell epigenetics affect biology and disease.


==========================================================================
The research, published in Genes & Development, has implications for
cancer research because it explains part of the paradox for how cells
can transcribe genes in the absence of high-energy sources, a situation
that unfolds in cancer and has puzzled researchers for years.

In the case of when cells have high amounts of energy, organisms make
high- energy molecules that fuel cell growth and division. In fact,
a property of cancer cells is having access to high amounts of sugar to
feed cancer growth.

In contrast, when cells run out of these "preferred" energy sources,
they will turn to other ways (or metabolic systems) to create energy
to stay alive. As is the case in dieting, cells will break down fats in
times of fasting. Cells are well equipped to deal with changing nutrient environments.

"But how cells adapt to these changes and initiate their specialized
gene expression programs to handle the new jobs created by the cell
under nutrient flux is one of the big mysteries in the field," said
Strahl, senior author of the paper and Oliver Smithies Investigator at UNC-Chapel Hill. To investigate how cells do this, Strahl's lab applied
a specialized lab system that allowed them to grow a naturally occurring
yeast in a chamber where they could precisely control the available energy sources. In doing so, they were able to force yeast to go through waves
of feast and famine that they could easily study. The waves of feast and
famine lead to waves of metabolic change, which allowed the researchers
to examine the details of what happened at the gene level.

All cells have the same genetic information or blue print of life but use
this information differently in order to create specialized functions --
for example, to create different cell types or tissues -- and to even
handle changes to the environment, such as energy flux. Decades of
research have revealed that the way different genes can be activated
within the genomic blueprint is through small chemical additions (or
molecular tags) to proteins called histones that wrap up our DNA. The
chemical signals or tags help to push the DNA to "open up" and turn a
gene on or "close down" and turn a gene off.

Yet, how changes in nutrient availably were able to "speak" to the genome
to instruct change in gene expression was poorly understood.

Using yeast as a model, Strahl lab graduate student Jibo Zhang led
experiments showing that under times of high energy, a byproduct
from metabolism helps drive up the levels of one molecular tag on the
histones. This process is called acetylation. In doing so, the researchers found that a newly identified domain in a protein that regulates the
expression of a gene called Yaf9 could bind this tag and bring with it
much of the machinery to create gene expression. However, during times of fasting, the situation became much different. The high energy tag on the histones was taken away to create critically needed energy for the cells.

But Zhang also found that the recruitment of Yaf9 was also gone. Although
this loss is normally thought to turn genes off, Zhang found that these
times were in fact high in the enzymes that drive gene expression. Thus,
cells found a way to still make gene expression happen under low nutrient conditions to address the need for gene expression without needing the
high energy histone tag.

This shows that cells have evolved a way to make sure gene expression
is still efficient at all times.

"We think the unique differences in the types of tags found between the
two nutrient states (high versus low) may in fact be a special type of
signal that makes sure gene expression programs are still efficient at
both times," said Zhang, first author of the paper.

This work has important implications for normal human biology and disease,
such as cancer. It is well known that cancer cells require high energy
sugars to maintain their growth and division. Much of cancer growth is metabolically driven.

The work from Strahl's lab provides new insights into the process of how
gene expression occurs under high energy conditions, which may open up
new therapeutic targets and ways to intervene to disrupt cancer growth.

Co-author of the Genes & Development paper is Aakanksha Gundu, an
undergraduate student at UNC-Chapel Hill. Brian Strahl is a member of
the UNC Lineberger Comprehensive Cancer Center.

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


========================================================================== Journal Reference:
1. Jibo Zhang, Aakanksha Gundu, Brian D. Strahl. Recognition of
acetylated
histone by Yaf9 regulates metabolic cycling of transcription
initiation and chromatin regulatory factors. Genes & Development,
2021; DOI: 10.1101/gad.348904.121 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211202113450.htm

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