Researchers focus spotlight on RNAs

Initially considered as a mediator between genes and proteins, RNA has been found to have a more complex role.

Eukaryotic genes consist of untranslated sequences and long noncoding RNAs (lncRNAs). The discovery of small RNAs regulating mRNA did not alter the perception of genomes as evolutionary waste, controlled mainly by transcription factors. 

However, recent research has revealed the specific functions of lncRNAs in cell and developmental biology, chromatin modification and phase-separated domains, despite their low conservation and genetic visibility. Most lncRNAs originate from "enhancers" to direct effector proteins to control cell fate decisions during development.

In 1977 a postdoctoral fellow was informed that the head of the lab did not believe that there were sequences in the middle of genes. However, it had been reported in the literature that these sequences, also known as introns, do exist, which explained why cDNA hybridization to genomic DNA was incongruent when analyzed using Southern blots. 

Because it was thought that genes consisted of a continuous string of base pairs, the discovery of introns came as a big surprise and even a little bit of a shock to the molecular biology community. This discovery contributed to a deeper comprehension of the information contained within genetic code.

Introns were thought to be manifestations of "junk DNA" even though they were transcribed. This was due to the deeply ingrained belief that genes and proteins were equivalent, which led to the idea that introns were nonfunctional despite being transcribed. 

On the other hand, the discovery of alternative splicing expanded the repertoire of protein isoforms, and introns eventually were rationalized as remnants of the initial gene assembly process. There was consideration given to the idea that intronic RNAs might play a regulatory role and be significant to the process of development. 

In the 1960s and 1970s, the idea of using RNA as a regulatory molecule was floated but was largely ignored due to the growing interest in transcription factors. In the 1980s and beyond, the discovery of small nuclear and nucleolar RNAs, in addition to other functional RNAs, shed light on the potential regulatory role of RNA in gene expression.

The decade of the 1980s saw the discovery of RNA catalysis in Tetrahymena, as well as bacterial RNaseP complexes and group II introns. Additionally, during this time period, the field of RNA structural biology began to flourish under the direction of multiple authorities. 

The functional repertoire of RNA has also been expanded due to the discovery of riboswitches and antisense regulatory RNAs. Given the limited genomic information and lack of tools to manipulate genes in vivo, the likelihood of successfully testing the functionality of RNAs that were removed from their respective introns was extremely low. 

Nevertheless, in the early 1990s a number of groups demonstrated that introns do not lack any function and that regulatory RNAs are a real phenomenon. The case for the functionality of introns was laid out in an article that was published in 1994 in the journal Current Opinion in Genetics and Development. The article suggested that introns have explored new genetic space and acquired functions that have provided positive pressure for their expansion. 

One of the reviewers expressed their excitement about the article and suggested that it should have a more eye-catching title. The phrase "efference RNA" (eRNA) was first used in 2000.

The realization that most of the genome, not just protein-coding genes, is transcribed in complex organisms was precipitated by the finding that microRNAs and piRNAs are processed from introns of protein-coding transcripts as well as both the exons and introns of long noncoding RNAs (lncRNAs). 

As a result of high-throughput cDNA sequencing, the identification of tens of thousands of long transcripts that have little to no potential to code for protein was made possible. Furthermore, at least 70% of mouse protein-coding genes have overlapping antisense transcripts. 

It was widely believed that transcription factors were sufficient to program developmental ontogeny, and the role of DNA and histone modifications in gene regulation was not yet fully appreciated, so the study of lncRNAs was met with skepticism about their relevance.