Protein Important in Diabetes May Also Play a Key Role in Heart Disease, Other Disorders
--Finding May Suggest Useful Drug Targets Among Gene Networks--
PHILADELPHIA, July 21 /PRNewswire-USNewswire/ -- Studying a
protein already known to play an important role in type 2 diabetes
and cancer, genomics researchers have discovered that it may have
an even broader role in disease, particularly in other metabolic
disorders and heart disease. In finding unsuspected links to other
disease-related genes, the scientists may have identified future
targets for drug treatments.
The paper appeared online July 17 in the British journal
Diabetologia.
"This protein could be a central player in many different
diseases and traits," said study leader Struan F.A. Grant, Ph.D., a
geneticist at The Children's Hospital of Philadelphia and a faculty
member of the University of Pennsylvania School of Medicine. The
current finding builds on Grant's 2006 discovery, now widely
replicated, that a gene called TCF7L2 is strongly linked to type 2
diabetes.
Type 2 diabetes results either when the pancreas produces
insufficient insulin or when the body's insulin-processing cells
develop resistance to insulin, causing blood sugar to rise to
unhealthy levels.
The TCF7L2 gene carries the code for a transcription
factor--also called TCF7L2--a protein that binds to genes and
regulates their activity. Exactly how this protein acts to affect
diabetes is still unknown. However, Grant noted that there is great
scientific interest in identifying which genes the transcription
factor regulates. "It may be more feasible to develop drugs aimed
at proteins encoded by specific gene classes regulated by TCF7L2
that are more amenable to targeted interventions, rather than
aiming at a more ubiquitous transcription factor," he said.
Because variants in the TCF7L2 gene are also associated with
risk for different cancers, including colorectal cancers, there was
even greater reason to learn details of its biological activity.
"Our goal," said Grant, "was to simply uncover the repertoire of
genes that this transcription factor controls."
Collaborating with investigators at the University of
Pennsylvania, Grant used a technique called ChIP-sequencing, which
locates and compiles the DNA sequences of genes to which proteins
bind. "This uses the latest-generation sequencing technology that
has only recently become feasible, allowing investigators to
rapidly sequence at the scale of whole genomes," said Grant. In
human cell lines, this ChIP approach identified and mapped DNA
sequences of TCF7L2 binding sites at over 1,000 gene
locations.
"What was unexpected and striking about our results was that
this transcription factor binds to a large number of gene locations
already implicated in disease from previous GWAS research," said
Grant. In the last five years, GWAS, or genome-wide association
studies, have proven to be highly successful in scouring the genome
to locate gene sites associated with particular diseases.
"We found an over-representation of genes associated with
metabolic disorders, such as diabetes, but also with cardiovascular
disorders, such as coronary artery disease and atherosclerosis,"
Grant added. "We expect to follow up these initial observations
with functional research to investigate how these genes operate in
these diseases, and whether these genes may become candidates for
better therapies. For now, our work suggests that this
transcription factor may be a central node in a network of genes
associated not only with type 2 diabetes, but also exerting its
influence much further in contributing to other genetic
diseases."
A grant from the Ethel Brown Foerderer Fund for Excellence from
The Children's Hospital of Philadelphia supported this study, with
added support from the National Institute of Diabetes, Digestive
and Kidney Disorders, the Penn Center for Musculoskeletal
Disorders, and the University of Pennsylvania Diabetes and
Endocrinology Research Center. Grant's co-authors were Klaus H.
Kaestner, Ph.D., Jonathan Schug, Ph.D., and Mingyao Li, Ph.D., of
the University of Pennsylvania; and Jianhua Zhao, Ph.D., of
Children's Hospital.
"Disease-associated loci are significantly over-represented
among genes bound by transcription factor 7-like 2 (TCF7L2) in
vivo," Diabetologia, published online July 17, 2010. doi:
10.1007/s00125-010-1852-3
About The Children's Hospital of Philadelphia: The Children's
Hospital of Philadelphia was founded in 1855 as the nation's first
pediatric hospital. Through its long-standing commitment to
providing exceptional patient care, training new generations of
pediatric healthcare professionals and pioneering major research
initiatives, Children's Hospital has fostered many discoveries that
have benefited children worldwide. Its pediatric research program
is among the largest in the country, ranking third in National
Institutes of Health funding. In addition, its unique
family-centered care and public service programs have brought the
460-bed hospital recognition as a leading advocate for children and
adolescents. For more information, visit http://www.chop.edu/.
Contact: John Ascenzi The Children's Hospital of Philadelphia Phone: (267) 426-6055 Ascenzi@email.chop.edu
Source: The Children's Hospital of Philadelphia
CONTACT: John Ascenzi, The Children's Hospital of
Philadelphia,
+1-267-426-6055, Ascenzi@email.chop.edu
Web Site: http://www.chop.edu/
Posted: July 2010
