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CSHL Team Finds microRNA Regulatory Role for Lin-42 in C. elegans

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NEW YORK (GenomeWeb) – Researchers from Cold Spring Harbor Laboratory (CSHL) this month reported new data showing that a C. elegans homolog of a human gene involved in circadian rhythms negatively regulates microRNA expression during the worms' development.

The findings indicate that the gene, lin-42, helps establish a cadence for miRNA-controlled developmental processes so that the worm's cells do what they are supposed to be doing without needing to communicate with each other, according to CSHL's Christopher Hammell, who led the research.

"All of these processes are reinforced so they can happen in a variety of environments and nutrient conditions," he told Gene Silencing News. "There is a system that is running in the background that speeds things up if it needs to or slows them down on a global scale so things can work properly."

This, he added, is "a property that I think will turn out to be conserved in a variety of organisms."

It has long been known that miRNAs play key roles in a variety of cellular and developmental processes via post-transcriptional regulation, and that the precise timing and level of their expression is critical.

In C. elegans, for instance, post-embryonic development proceeds through a series of four larval stages during which the temporal and spatial patterns of cell division and differentiation are "tightly orchestrated and invariant," Hammell and his team wrote in their paper, which appeared in PLOS Genetics.

Heterochronic genes direct these temporal patterns of development, and many of these are regulated by miRNAs that are expressed at different times to block earlier patterns of development and open the door to later gene expression profiles. Yet the molecular mechanism behind this is largely unknown.

Given that miRNAs' effects on target genes are dose dependent, Hammell — previously a postdoc in the lab of miRNA pioneer Victor Ambros — and his colleagues speculated that there must exist a system by which miRNA expression is not only switched on and off, but kept within a certain threshold.

As such, they undertook a series of forward genetic screens to look for negative regulators of miRNA expression during different stages of C. elegans development.

Their experiments identified lin-42, the homolog of the circadian gene known as period, as a modulator of heterochronic miRNA expression and a regulator of a wide range of broadly expressed, and functionally distinct, miRNAs in the worm.

So while lin-42 and period have different functions, they both serve to regulate transcription in an oscillatory manner — the former is involved in making cell fate decisions that occur only during specific developmental stages while the latter controls cyclical biological processes.

In their study, the scientists identified five new alleles of lin-42 that suppress the adult-specific gene expression defects of hypomorphic alleles of heterochronic miRNAs, and discovered that the gene corrects stage-specific cell fate specification defects present throughout larval and adult development in these miRNA mutants.

This, they wrote, suggests that lin-42 "broadly functions to negatively regulate miRNA expression [and] is therefore is likely to act in a variety of pathways that require miRNAs for proper cell fate specification." Consistent with this, they found that lin-42 also plays a role in the miRNA-mediated specification of asymmetric gene expression patterns in gustatory neurons. Further, an analysis of lin-42's interactions with chromatin suggests that it "potentially regulates the transcription of both miRNAs and mRNAs," according to the paper.

Hammell and his group also created special transcriptional reporters that they used to show that lin-42 mutations alter the expression of lin-4 and let-7 — two of the first discovered miRNAs. Surprisingly, loss-of-function mutations in lin-42 mutants did not abolish the oscillatory patterns of these miRNAs' expression but rather increased them.

Based on their findings, the investigators concluded that a key function of lin-42 is to "dynamically inhibit the transcription of post-embryonically expressed miRNAs and mRNAs to ensure the robustness of developmental gene expression." And because every miRNA potentially regulates a large number of different genes, lin-42's impact on the dynamic nature of the C. elegans transcriptome during development "may be immense."

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