Cholesterol Trafficking in the Mouse Embryo Is Regulated by a snoRNA

There are two main classes of snoRNA, the C/D box snoRNAs, which are associated with methylation, and the H/ACA box snoRNAs, which are associated with pseudouridylation. Pseudouridine is the C-glycoside isomer of the nucleoside uridine, and it is the most prevalent of the over one hundred different modified nucleosides found in RNA

Investigators at Washington University School of Medicine (St. Louis, MO, USA) used a loss-of-function screening test to look for Chinese hamster ovary cell mutants with defects in intracellular cholesterol trafficking. They isolated a mutant with haploinsufficiency of U17 snoRNA. U17 is an H/ACA orphan snoRNA, for which a function other than ribosomal processing had not previously been identified.

The investigators published results in the June 2, 2015, issue of the journal Cell Metabolism revealing that through expression profiling they had identified HUMMR (hypoxia-upregulated mitochondrial movement regulator) mRNA as a target that was negatively regulated by U17 snoRNA. In experiments conducted on U17 snoRNA-deficient cells, they found that upregulation of HUMMR promoted the formation of ER (endoplasmic reticulum)-mitochondrial contacts, decreasing esterification of cholesterol, and facilitating cholesterol trafficking to mitochondria.

In contrast, in cells that had an abundance of U17 snoRNA, cholesterol was not transported to the mitochondria, and without this raw material, the cells could not synthesize any steroids.

These findings relating to interactions at the molecular level confirmed previous observations that at birth, mice have high levels of U17 snoRNA, which gradually decline as the animals grow and mature. When the mice reach sexual maturity—at about eight weeks—U17 snoRNA levels have fallen, which increases production of steroid hormones.

"The ovaries need to make steroids to support pregnancy when the mice reach sexual maturation. So we think this small RNA is at least one of the regulators of the processes that govern when a mouse becomes fertile," said senior author Dr. Daniel S. Ory, professor of medicine at the Washington University School of Medicine. "This is one of several hundred snoRNAs. Clearly, some of them have functions beyond the traditional understanding of snoRNAs, and perhaps they should be studied more systematically."

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