Pediatric（小儿科的） researchers have discovered a new biological pathway in which small segments of RNA, called microRNA, help protect red blood cells from injury caused by chemicals called free radicals1（自由基） . The microRNA seems to have only a modest role when red blood cells experience normal conditions, but steps into action when the cells are threatened by oxidant（氧化剂） stress. Led by hematologist（血液学家） Mitchell Weiss, M.D., Ph.D., of The Children's Hospital of Philadelphia, the current study describes how a particular microRNA fine-tunes gene3 activity by acting4 on an unexpected signaling pathway.
The study appears in the August 1 issue of the journal Genes5 & Development, simultaneously6 with a similar study of microRNAs and red blood cells by a University of Texas team led by Eric Olson, Ph.D. The two studies reinforce each other, said Weiss.
MicroRNAs are single-stranded molecules8 of ribonucleic acid (RNA核糖核酸) averaging only 22 nucleotides（核苷酸） long. Scientists estimate that 500 to 1000 microRNAs exist in the human genome. First characterized in the early 1990s, they received their current name in 2001. Over the past decade, scientists have increasingly recognized that microRNAs play a crucial role in regulating genes, most typically by attaching to a piece of messenger RNA and blocking it from being translated into a protein, but many details remain to be discovered.
"Although microRNAs affect the formation and function of most or all tissues, for most microRNAs, we don't know their precise mechanisms9 of action," said Weiss. "In this case we already knew this microRNA, called miR-451, regulates red blood cells in zebrafish and mice, and because it is highly conserved10 in evolution, we presume it operates in humans as well. But its functional11 roles were poorly understood."
By investigating how microRNAs influence red blood cell development, Weiss and colleagues aimed to understand how such development goes wrong in hemolytic anemia12（溶血性贫血） , in which red blood cells are destroyed in large numbers, or in disorders13 of abnormal blood cell production. The current study used knockout mice—bioengineered animals in which the miR-451 gene was removed and could not function.
They found that preventing the activity of miR-451 produced only modest effects—mild anemia in the mice—but when the team subjected mice to oxidant stress by dosing them with a drug that produces free radicals, the mice had profound anemia. The oxygen radicals attacked hemoglobin（血红蛋白） , the iron-carrying molecule7 in red blood cells.
"This is a common theme in microRNAs—frequently, they don't play a central role during tissue formation or normal conditions, but they have a strong protective effect when an organism is stressed," said Weiss. "Over evolutionary14 time, red blood cells have evolved ways to protect themselves; one of those ways is the action of microRNA."
Weiss's team found that miR-451, acting through intermediate（中间的，中级的） steps on a signaling pathway, affects a key protein, FoxO3. As a transcription factor, FoxO3 regulates hundreds of genes; in this case, FoxO3 stimulates15 specific genes that protect red blood cells from oxidant stress. The knockout mice in this study, having lost miR-451's function, showed impaired16 FoxO3 activity, and less ability to protect their red blood cells.
The regulatory pathway seen here, Weiss added, may have medical implications beyond blood cell development. "This finding does not have immediate17 clinical application for patients with blood diseases, but it sheds light on how microRNAs fine tune2 physiological18 functions in different contexts," said Weiss. FoxO3 regulates anti-oxidant functions in heart cells and also acts as a tumor19 suppressor, so miR-451 may have an important role in heart protection and in fighting cancers. "Further studies may broaden our knowledge of how this microRNA may defend the body against disease," he added.
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