Nav: Home

Microbes seen controlling action of host's genes

May 17, 2017

DURHAM, N.C. -- All animals -- from sea sponges to modern-day humans -- evolved in a world already teeming with microbes. These single-celled microorganisms now cover practically every surface of our bodies and are as much a part of our biology as our own tissues and organs. They educate our immune system, regulate our metabolism, and as it turns out, even influence our behavior.

Duke researchers have shown that microbes can control the actions of their animal hosts by manipulating the molecular machinery of animal cells, triggering patterns of gene expression that consequently contribute to health and disease. The work, which was conducted in zebrafish and mice, could have implications for human inflammatory bowel diseases like Crohn's disease and ulcerative colitis. The findings appear in the journal Genome Research.

"Our results suggest that ancient parts of our genome and ancient interactions with our microbes are relevant to modern-day human diseases," said John F. Rawls, Ph.D., senior author of the study and associate professor of molecular genetics and microbiology at Duke University School of Medicine.

In recent years, scientists have uncovered abundant links between our trillions of resident bacteria, viruses and fungi -- known collectively as the microbiome -- and a spectrum of human conditions, ranging from anorexia to diabetes. But Rawls says important gaps remain in our understanding of how these microbes influence health and cause disease in humans as well as other members of the animal kingdom.

Rawls takes what he calls an "evolutionary conservation" approach to identify the genetic underpinnings of distantly related animals that may also be relevant to human health. In this study, Rawls investigated the impact that the microbiome might have on an animal's genome by studying specific regions of the genome that regulate which genes are turned on or off at a given time or in a given tissue. Some of these regions might keep the strands of DNA packaged into tight coils, hiding them from the machinery responsible for translating the genetic code. Others -- known as enhancers -- recruit special proteins called transcription factors to designated sites around a gene to turn it on.

A graduate student in the Rawls lab, James M. Davison, compared these genetic regions in two sets of mice: one that was germ-free and one that had their bellies loaded with microbes. He discovered that a large number of enhancers behaved differently in the presence of microbes. When he looked closer, he found that some of these elements bound a protein called Hnf4a, an ancient animal transcription factor that had previously been implicated in a number of human diseases, including inflammatory bowel diseases, obesity and diabetes.

By comparing gene sequences between different animal species, including humans, mice and zebrafish -- Davison was able to show that throughout evolution, Hnf4a appears to protect against microbial contributions to inflammatory bowel diseases. Davison went on to show that microbes can partially disable Hnf4a in mice and zebrafish and perhaps obstruct its protective role. When Hnf4a is fully disabled, microbes stimulate patterns of gene expression in animals that are associated with inflammatory bowel diseases.

"We found microbes exert a previously unappreciated influence on a transcription factor that shares a very old and interesting place in our heritage as animals, but also is clearly involved in human disease," said Davison, who is lead author of the study. "That we observed similar effects in zebrafish and mice suggests that this is a common feature of host-microbe interactions that might have existed in our common (vertebrate) ancestors."

The researchers still don't know exactly how microbes disable Hnf4a, but they have a number of hypotheses. For example, microbes might somehow block the protein's landing spots on the DNA, or they might inactivate the protein's DNA binding activity by modifying the protein itself. They also don't know if specific subsets of microbes are more manipulative than others. Rawls says that if they can figure that out, it could point to new microbial or pharmaceutical strategies for restoring Hnf4a's protective powers to promote human health.
This work was supported by the National Institutes of Health (R01-DK081426, U24-DK097748, P01-DK094779, R24-OD016761, and P30-DK34987).

CITATION: "Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha," James M. Davison, Colin R. Lickwar, Lingyun Song, Ghislain Breton, Gregory E. Crawford and John F. Rawls. Genome Research. Advance Online May 17, 2017. DOI:10.1101/gr.220111.116

Duke University

Related Genome Articles:

A close look into the barley genome
An international consortium, with the participation of the Helmholtz Zentrum München, Plant Genome and Systems Biology Department (PGSB), has published methodologically significant data on the barley genome.
Barley genome sequenced
Looking for a better beer or single malt Scotch whiskey?
From Genome Research: Pathogen demonstrates genome flexibility in cystic fibrosis
Chronic lung infections can be devastating for patients with cystic fibrosis (CF), and infection by Burkholderia cenocepacia, one of the most common species found in cystic fibrosis patients, is often antibiotic resistant.
A three-dimensional map of the genome
Cells face a daunting task. They have to neatly pack a several meter-long thread of genetic material into a nucleus that measures only five micrometers across.
Rhino genome results
A study by San Diego Zoo Global reveals that the prospects for recovery of the critically endangered northern white rhinoceros -- of which only three individuals remain -- will reside with the genetic resources that have been banked at San Diego Zoo Global's Frozen Zoo®.
Science and legal experts debate future uses and impact of human genome editing in Gender & the Genome
Precise, economical genome editing tools such as CRISPR have made it possible to make targeted changes in genes, which could be applied to human embryos to correct mutations, prevent disease, or alter traits.
Genome: It's all about architecture
How do pathogens such as bacteria or parasites manage to hide from their host's immune system?
Accelerating genome analysis
An international team of scientists, led by researchers from A*STAR's Genome Institute of Singapore and the Bioinformatics Institute, have developed SIFT 4G (SIFT for Genomes) -- a software that can lead to faster genome analysis.
Packaging and unpacking of the genome
Single-cell techniques have been used to investigate histone replacement and chromatin remodeling in developing oocytes.
The astounding genome of the dinoflagellate
Dinoflagellates live free-floating in the ocean or symbiotically with corals, serving up -- or as -- lunch to a host of mollusks, tiny fish and coral species.

Related Genome Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...