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Genomics in the Journals: 2014.03.13

NEW YORK (GenomeWeb News) – While variants in the gene FTO have previously been associated with a propensity toward obesity, the University of Chicago's Marcelo Nóbrega and colleagues reported in Nature this week that those obesity-linked variants in FTO actually form long-range functional connections with the homeobox gene IRX3.

"Our data strongly suggest that IRX3 controls body mass and regulates body composition," Nóbrega said in a statement. "Any association between FTO and obesity appears due to the influence of IRX3."

IRX3 encodes a transcription factor that is expressed in the brain.

Using circular chromosome conformation capture followed by high-throughput sequencing, the researchers mapped the cis-regulatory circuitry of the FTO locus in mice, finding that it interacts with the promoters of other genes, including IRX3. They confirmed the interaction between IRX3 and FTO using chromosome conformation capture in adult mouse brains.

Additionally, drawing on more than 150 human brain samples, Nóbrega and colleagues found obesity-linked SNPs are associated with IRX3, rather than FTO, expression. And the obesity-linked SNPs in FTO introns appeared to act as enhancers of IRX3 function, though the FTO gene itself did not.

Turning to mouse models, the researchers found that IRX3-deficient mice weigh some 25 percent to 30 percent less than their non-deficient counterparts, mainly through a loss of fat mass and an increase of brown fat.

Further, IRX3 is expressed in the hypothalamus, in a region known to be involved in the regulation of energy homeostasis.

"IRX3 is probably a master regulator of genetic programs in the cells where it is expressed," Nóbrega added. "We're interested in what its targets are and what they alter. The goal is to identify downstream targets of IRX3 that become models for drug targeting."

A 10-lipid signature may be able to predict whether someone will develop mild cognitive impairment or Alzheimer's disease in the next two to three years, according to researchers from Georgetown University and the University of Rochester.

Georgetown's Howard Federoff and colleagues wrote in Nature Medicine this week that their blood test is about 90 percent accurate in its predictions.

"Our novel blood test offers the potential to identify people at risk for progressive cognitive decline and can change how patients, their families, and treating physicians plan for and manage the disorder," Federoff said in a statement.
To develop this test, the researchers enrolled 525 people over the age of 70 into a five-year observational study and collected blood samples. Over the course of the study, 74 participants met the criteria for amnestic mild cognitive impairment (aMCI) or mild Alzheimer's disease (AD).

Using a subset of that population, the researchers searched for biomarkers that distinguished those that developed aMCI or AD from those that did not using an untargeted metabolomic approach. According to their analyses, 10 metabolites — including phosphatidylcholine (PC) and acylcarnitine (AC) — could discriminate participants who developed aMCI or AD within two to three years from those who did not.

The researchers confirmed their findings in a separate group of 40 participants that included 10 converters.

PC and AC, the researchers said, have key functions in the structure, integrity, and functionality of cell membranes.

"We posit that this ten–phospholipid biomarker panel, consisting of PC and AC species, reveals the breakdown of neural cell membranes in those individuals destined to phenoconvert from cognitive intactness to aMCI or AD," Federoff and colleagues said in their paper, "and may mark the transition between preclinical states where synaptic dysfunction and early neurodegeneration give rise to subtle cognitive changes."

The researchers noted that their biomarker panel requires further validation before it can be applied in the clinic.

Lund University researchers developed a methylome map of human pancreatic islets cells from patients with and without type 2 diabetes, work that they described in PLOS Genetics.

Using the Infinium HumanMethylation450 BeadChip, the researchers also uncovered more than 1,600 CpG sites and 850 genes with differential methylation in T2D islets, and a number of those changes appeared to be linked to decreased insulin production.

"This shows that the risk of developing type 2 diabetes is not only genetic, but also epigenetic," senior author Charlotte Ling said in a statement.
For instance, she and her colleagues noted that 17 candidate T2D genes — including TCF7L2, THADA, KCNQ1, FTO, and IRS1 — showed differential DNA methylation in T2D islet cells.

The researchers suggested that genetic and epigenetic mechanisms may interact to influence T2D susceptibility.

They found that T2D risk factors like hyperglycemia, aging, and BMI were also linked to differential DNA methylation in islets from non-diabetic research participants. Differential DNA methylation, the researchers said, could predispose someone to disease. They cautioned, though, that they couldn't rule out that some differences could be secondary to the disease or epiphenomenon.

"It shows that epigenetics is of major significance for type 2 diabetes, and can help us to understand why people develop the condition," Ling added. "This also opens the way for the development of future drugs."

Inhibition of a microRNA may improve cardiac function during heart failure, researchers led by Mark Mercola at the University of California, San Diego, and the Sanford-Burnham Medical Research Institute, reported in Nature.

The miRNA — miR-25 — blocks SERCA2a, a calcium-transporting ATPase that is integral for calcium uptake during excitation-contraction coupling in heart cells. Decreased SERCA2a activity is one cause of poor heart contractions and the enlargement of the heart muscle that leads to heart failure.

"In this study, we have not only identified one of the key cellular processes leading to heart failure, but have also demonstrated the therapeutic potential of blocking this process," co-first author Dongtak Jeong from the Icahn School of Medicine at Mount Sinai said in a statement.

The researchers conducted a high-throughput functional screen of the human microRNAome to uncover miRNAs that down regulate the calcium pump of the heart. From this, they homed in on miR-25.

In both mouse and human cardiomyocytes, miR-25 delayed calcium uptake and overexpression of miR-25 led to a loss of contractile function. Additionally, an antisense oligonucleotide against miR-25 appeared to stop heart failure in a mouse model.

This, the researchers said, suggests that inhibition of miR-25 may be a new therapeutic strategy to treat heart failure.