MicroRNA regulation is biased toward development

MicroRNAs are short sequences (several sources put them at 21 to 25 nucleotides) of noncoding RNA MicroRNA function is a fairly new discovery, with their existence, diversity and operation characterized only within the last five years. A good review was provided by Lin He and Gregory Hannon (2004), which is now getting to be a little old, but covers the basics.

These little RNA snippets may function in many ways. At least some of them function as gene regulatory mechanisms, by interfering with the translation of messenger RNA (mRNA). Interference happens when part of the microRNA complements a small part of an mRNA sequence, and binding between the two effectively represses protein synthesis at the ribosomes. MicroRNAs themselves are results of posttranscriptional processing from longer precursor RNAs, which have a three-dimensional structure that gets cut down

Gene expression and regulation is certainly the "in" topic in genomics, because it is the major unknown connector between genes, phenotypes, and development. MicroRNA regulation is one of the hottest topics in gene regulation, because they are new, cute, and cool. They also get a lot of attention because a few microRNAs can interfere with the normal processes of regulated cell death (apoptosis), and thereby help to cause cancers.

One other thing: "microRNA" is just too long for molecular biologists to type, so they are abbreviated "miRNA".

It has been known for a few years that at least some miRNAs were highly active during the development of the brain in mammals (e.g., Krichevsky et al. 2003). For example, Miska and colleagues (2004) found that microRNA expression pulsed in waves through the developing mouse brain:

We isolated 18-26 nucleotide RNAs from developing rat and monkey brains. From the sequences of these RNAs and the sequences of the rat and human genomes we determined which of these small RNAs are likely to have derived from stem-loop precursors typical of microRNAs. Next, we developed a microarray technology suitable for detecting microRNAs and printed a microRNA microarray representing 138 mammalian microRNAs corresponding to the sequences of the microRNAs we cloned as well as to other known microRNAs. We used this microarray to determine the profile of microRNAs expressed in the developing mouse brain. We observed a temporal wave of expression of microRNAs, suggesting that microRNAs play important roles in the development of the mammalian brain.

MicroRNAs seem to be involved in many different kinds of developmental processes, many of them embryonic -- such as Hox-mediated development -- but also adult functions such as hematopoiesis (Pasquinelli et al. 2005).

Zhenbao Yu and colleagues compared the expression of microRNA targets in adult and developing embryonic tissues of mice and flies. The miRNA targets are the mRNA sequences that the miRNA binds. In other words, these are the genes that are regulated by miRNA, and -- as the results show -- they are more highly expressed during embryonic development. Here's their abstract:

MicroRNAs (miRNAs) are non-coding small RNAs of 22 nt that regulate the gene expression by base pairing with target mRNAs, leading to mRNA cleavage or translational repression. It is currently estimated that miRNAs account for 1% of predicted genes in higher eukaryotic genomes and that up to 30% of genes might be regulated by miRNAs. However, only very few miRNAs have been functionally characterized and the general functions of miRNAs are not globally studied. In this study, we systematically analyzed the expression patterns of miRNA targets using several public microarray profiles. We found that the expression levels of miRNA targets are lower in all mouse and Drosophila tissues than in the embryos. We also found miRNAs more preferentially target ubiquitously expressed genes than tissue-specifically expressed genes. These results support the current suggestion that miRNAs are likely to be largely involved in embryo development and maintaining of tissue identity.

This kind of expression survey at different ontogenetic stages is very important, because it covers a blind spot in analyses that depend on functional categories. For example GO analyses include categories for "development", but as Yu and colleagues point out, many genes change in expression during development that are not part of the "developmental" categories. This is another of the consequences of widespread pleiotropy -- genes that have important effects early in development may continue to be important in restricted tissues later in life. By being scored in a functional category related to these later functions, the earlier functions of the gene may be missed in the functional analysis. Screening gene expression at multiple times helps to catch these temporally sensitive functions.

References:

He L, Hannon GJ. 2004. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 5:522-532. doi:10.1038/nrg1379

Krichevsky AM, King KS, Donahue CP, Khrapko K, Kosik KS. 2003. A microRNA array reveals extensive regulation of microRNAs during brain development. RNA 9:1274-1281.

Miska EA, Alvarez-Saavedra E, Townsend M, Yoshii A, Sestan N, Rakic P, Constantine-Paton M, Horvitz HR. 2004. Microarray analysis of microRNA expression in the developing mammalian brain. Genome Biol 5:R68. Free full text

Pasquinelli AE, Hunter S, Bracht J. 2005. MicroRNAs: a developing story. Curr Opin Genet Dev 15:200-205.

Yu Z, Jian Z, Shen S-H, Purisima E, Wang E. 2007. Global analysis of microRNA target gene expression reveals that miRNA targets are lower expressed in mature mouse and Drosophila tissues than in the embryos. Nucleic Acids Res 35:152-164. doi:10.1093/nar/gkl1032