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ChIP-Seq Study Uncovers Vitamin D Receptor Binding Sites

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Vitamin D seems to influence the activity of scores of genes across the genome and may influence some genes implicated in some human diseases, including some autoimmune conditions and cancers, according to a new study in which researchers mapped vitamin D receptor binding sites across the genome and gauged vitamin D-related expression patterns.

An international research team led by investigators at the Wellcome Trust Centre for Human Genetics used chromatin immunoprecipitation coupled with massively parallel sequencing to find nearly 3,000 vitamin D receptor binding sites in cells treated with active vitamin D. Many of these sites seemed to cluster near genes linked to human diseases and other traits through past genome-wide association studies, they noted.

The study, which appeared online last night in Genome Research, also identified more than 200 genes with altered expression in the presence of the vitamin.

"Motivated by the biological and clinical significance of vitamin D-mediated gene regulation, we present … a comprehensive ChIP-Seq genomic map of [vitamin D receptor-DNA] binding and gene regulation in lymphoblastoid cell lines," the researchers wrote, "and show how this provides insights into genetic susceptibility to disease."

Vitamin D contributes to calcium homeostasis and bone development and is produced by the body following exposure to sunshine. It is also found naturally in certain foods, such as oily fish.

Some research suggests populations living in parts of the world with less sunshine have evolved lighter skin and hair color as a means of amping up vitamin D production. And vitamin D deficiency, which can lead to bone problems such as rickets, has been suggested as a possible contributor to a range of other conditions, including autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

"Vitamin D status is potentially one of the most powerful selective pressures on the genome in relatively recent times," co-corresponding author George Ebers, a genetics and clinical neurology researcher affiliated with the Wellcome Trust Centre for Human Genetics and the University of Oxford, said in a statement.

"Our study appears to support this interpretation and it may be we have not had enough time to make all the adaptations we have needed to cope with our northern circumstances," he added.

In an effort to untangle vitamin D's influence on health and disease, the team did ChIP-Seq using the Illumina Genome Analyzer II to sequence DNA associated with the nuclear vitamin D receptor in two lymphoblastoid cell lines before and after treatment with calcitriol — the active form of vitamin D.

Interactions between calcitriol and the vitamin D receptor prompt the receptor to couple with another receptor, the retinoid X receptor, to influence gene expression, the researchers explained. The cell lines tested had been generated from samples collected from Caucasian individuals as part of the International HapMap effort.

Their search uncovered a slew of new and previously reported vitamin D receptor binding sites. Prior to calcitriol stimulation, for example, they found vitamin D receptor binding sites in 623 areas in the genome. That jumped to 2,776 binding sites in cells treated with active vitamin D.

Calcitriol stimulation increased the number of vitamin D receptor binding sites both within and between genes. But binding sites seemed to be more common in parts of the genome with active chromatin and in regions of apparent positive selection in Asian and European genomes.

"The reasons behind this are unclear," the researchers wrote, "but one suggestion is that evolutionary pressure has maintained vitamin D binding in some regions of the genome as humans migrated out of Africa."

And the team's comparison with the Catalog of Published Genome-Wide Association Studies suggests many of the binding sites cluster in and around genes previously implicated in autoimmune conditions (including multiple sclerosis, Crohn's disease, systematic lupus erythrematosus, and rheumatoid arthritis), some cancers (particularly chronic lymphocytic leukemia and colorectal cancer), and traits such as hair color and height.

For instance, the researchers noted that they found vitamin D receptor binding sites in a multiple sclerosis-associated gene called IRF8 as well and in PTPN2, a gene linked to Crohn's disease and type 1 diabetes.

Meanwhile, the team's microarray experiments identified 226 genes found at higher levels in the presence of active vitamin D and three showing decreased expression in the vitamin stimulated cells.

Though they noted that more research is needed to tease apart the functional bases for some of the interactions detected, those involved in the study argue that their findings support the notion that vitamin D supplements may be beneficial for some individuals.

"There is now evidence supporting a role for vitamin D in susceptibility to a host of diseases," lead author Sreeram Ramagopalan, a researcher affiliated with the Wellcome Trust Centre for Human Genetics, the University of Oxford, and Queen Mary University of London, said in a statement. "Vitamin D supplements during pregnancy and the early years could have a beneficial effect on a child's health in later life."

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