Nature: Diabetes-inducing genes can be regulated like rheostos

Researchers at the Centre for Genome Regulation (CRG) and Imperial College London have discovered a switch
that regulates the activity of genes that cause diabetes.
The findings, published in Nature Cell Biology, point to potential new weaknesses in the disease and could lead to the development of
new therapeutic strategies.


HNF1A is a gene
that provides instructions for making a protein called hepatocyte nuclear factor-1 α.
This protein is expressed in many tissues, but is especially important for the pancreas, where it plays a role
in the development of pancreatic β cells.
β cells produce the hormone insulin,
which regulates blood sugar levels.


Mutations in HNF1A cause cells to produce a protein that doesn't work properly, which in turn affects the function of
β cells.
This has led some people to develop a disease known as "mature diabetes in young adults," which develops symptoms
such as high blood sugar before the age of 30.


Although the disease accounts for only 1% of all types of diabetes, it is high in absolute numbers due to the high
prevalence of diabetes in the global population (5-10%).
Along with other genetic and non-genetic factors, HNF1A is also known to play a key role
in susceptibility to the more common type 2 diabetes.


Understanding how the HNF1A gene is turned on or off in β cells could be important for understanding why a defect in the gene causes diabetes, or how it can be used to correct underlying problems
.
By combining mouse and human models, the researchers are now focusing on a mysterious part of the genome near HNF1A with unique functions
that have never been described before.
This DNA regulatory element works like a rheostat; If the HNF1A gene is transcribed too much, it will decrease transcription, and if the gene transcription is lax, it will resume transcription
.


Jorge Ferrer, Senior Researcher at CRG and Group Leader of the CIBERDEM Group, explains: "We named it a stabilizer, in contrast to other DNA regulatory elements such as enhancers, promoters and sileners, and called this particular element HASTER, or HNF1A stabilizer
.
"

The vast majority of RNA molecules synthesized in cells do not encode proteins
.
HASTER CONTROLS THE PRODUCTION
OF A CLASS OF RNA MOLECULES CALLED LONG NONCODING RNA (LNCRNAs).
"It's interesting because there are thousands of lncRNAs in the human genome, most of which have no known function
.
It is likely that there are many lncrRNAs in our genome that have similar functions
to HASTER.
If so, they could play an important role in human disease," said
Dr Anthony Bocher, lead author of the study.


THE RESEARCHERS FOUND THAT MUTATIONS IN THE HASTER GENE CAUSED DIABETES
IN MICE.
"THIS IS IMPORTANT BECAUSE IT PROVES THAT ELEMENTS OF THIS TYPE ARE EXTREMELY IMPORTANT AND THAT THE CONSEQUENCES OF REMOVING HASTER ARE COMPARABLE
TO THE REMOVAL OF HNF1A itself.
" HASTER may be an effective way to
deal with HNF1A.
Dr.
Ferrer said
.


This study is an example of how studying non-protein-coding sequences in the genome can lead to new ways to
understand and treat disease.
Only 1-2% of the human genome consists of
protein-coding sequences.
The rest of the "dark matter" is thought to include thousands of regions
that regulate gene expression.


THE RESEARCHERS FOUND THAT ALTERING THE FUNCTION OF GENE REGULATORY ELEMENTS, SUCH AS HASTER, CAN DRAMATICALLY ALTER CELLULAR FUNCTION, JUST AS IT DOES DISRUPT THE GENE ITSELF, PAVING THE WAY
FOR FUTURE EXPLORATION OF THE ROLE OF NONPROTEIN-CODING SEQUENCES IN PROMOTING DISEASE.

"There is much
more space in the human genome for regulating genes than for genes themselves.
In this study, we experimentally validated only one region to determine its function
.
This is likely to be just the tip of the iceberg," Dr.
Feller concluded
.