RNA in Disease and development

KEYWORDS:

• RNA in disease
• RNA processing
• RNA regulators
• RNA stability

The past decades in RNA research have unveiled a plethora of activities that RNAs can fulfill besides coding for proteins. These range from catalysis, over scaffolding to regulatory functions. Together with their ability to self-replicate has led to the hypothesis of an RNA world, where functions that are now generally attributed to proteins needed to be performed by RNAs. Consequently, it is not surprising that also modern cells in all kingdoms of life contain different classes of RNAs with various activities that are of great importance for cellular function and development.

While mutations in DNA that affect the protein coding regions of genes and cause pathologies are intensively studied since the onset of molecular biology, the role of various classes of non-coding RNAs and their impact on disease development is much less understood. Driven by innovative method developments, the study of different classes of RNAs, their modes of action and their impact on normal development and disease has recently experienced a great expansion. This timely special issue of RNA Biology now brings together reviews and research articles that cover different classes of RNAs, their biologic function and their impact on normal and pathologic development.

Bacteria have developed a complex network of regulatory RNAs such as sRNAs, riboswitches and antisense RNAs to respond to metabolic stimuli but also to control pathogenic life cycles. Importantly, these RNA networks are themselves regulated by RNA binding proteins and RNA metabolizing enzymes. The complexity of these networks during infectious cycles are reviewed by Pascale Cossart¹ revealing new concepts in bacterial riboregulation in the complex life cycles of Listeria monocytogenes. This is complemented by a review of Petra Dersch² describing riboregulation during infection of E.coli, Salmonella, Shigella and Yersinia that discusses efforts to combat these infections by targeting RNA based regulons.

Eukaryotic miRNAs are important regulators of RNA translation and stability playing decisive functions in cell division, apoptosis and cellular differentiation. Two examples are described in this issue. A study by Liu et al.³ defines Ago2 associated miRNA profiles during neuronal regeneration after ischemic insult that can regulate neuronal proliferation. Another research paper by McMullen and colleagues⁴ studies the effect of novel treatments against heart disease that target the miR-34 family. The authors identify transcription factors and novel downstream miRNAs as targets of the novel therapy.

An exciting mechanism to regulate endogenous miRNAs is the sponge-effect exerted by circular RNAs. A review by Jun Shen⁵ summarizes current knowledge on the biogenesis and turnover of circRNAs and their impact on oncogenesis but also gives perspective to potential circRNA based therapies.

Long non-coding RNAs are another class of RNAs that have been linked with several diseases. While the diagnostic potential of lncRNAs is obvious, their functional implication in diseases such as cancer and their potential role as targets for therapies is not well understood. A review by Utpal Bhadra⁶ summarizes the current understanding on the biogenesis and potential function of this rapidly growing class of lncRNAs.

RNA-seq has led to a much refined diagnostic of tumors and supported the discovery of novel-tumor specific transcripts. Human epidermal growth factor (HER-2) is overexpressed in an aggressive form of breast tumors. Alternative splicing of the her-2 transcript can lead to the inclusion of intron 8 which translates into Herstatin that acts as a tumor suppressor. Alison Tyson-Capper⁷ identifies hnRNP A1 as a major factor that leads to inclusion of intron 8 while splicing factor SRSF1 antagonizes intron 8 inclusion, demonstrating the important role of competing RNA binding proteins and splicing factors in disease development. The global role of splicing factors in disease development is addressed in a review by David Staněk⁸ which also addresses the puzzling question why mutations in global splicing factors show very specific phenotypes such as retinitis pigmentosa.

Interestingly, IRES-dependent translation of key cell fate affecting proteins has been implicated in tumorigenesis. A research paper by Thakor et al.,⁹ shows how IRES-mediated translation of the X-linked inhibitor of apoptosis is controlled by the simultaneous recruitment of PABP and eIF3.

RNA binding proteins not only control processing, turnover and translation of RNAs but are also involved in very complex processes such as long-term memory consolidation. Mani Ramaswami¹⁰ provides an interesting overview on this emerging topic and discusses long-term memory formation by the prion-like domains of the Cytoplasmic Polyadenylation Element Binding (CPEB) protein and other RNA-binding proteins that may regulate the translational state of critical synaptic RNAs.

RNA modifications are important regulators of the fate, immunogenicity but also coding potential of RNAs. Adenosine deamination by ADARs is the most abundant form of RNA modification that can affect coding, processing and turnover of RNAs. The group of Gideon Rechavi¹¹ provides further evidence that adenosine deamination is also required to suppress immune stimulation by endogenous RNAs. A liver specific knock out of ADAR1 leads to inflammation with increased expression of pro- inflammatory cytokines.

Cytidine deamination by overexpressing APOBEC3A can affect hundreds of genes. The group of Baysal¹² maps candidate APOBEC3G editing sites in HEK293 cells and demonstrates recoding in hundreds of mRNAs demonstrating the regulatory potential of APOBEC3A.

The archetype of RNA editing was identified in Trypanosomes where kinetoplastid (mitochondrial) RNAs need to be heavily edited by introducing and deleting hundreds of uridines to generate functional mRNAs. Key enzymes in this reaction are terminal uridylyl transferases (TUTases) that are responsible for the non-templated insertion of uridines. As kinetoplastid editing is essential for trypanosomes, specific inhibitors have long been searched for. The group of Beth Thomas¹³ reports on the identification of TUTase inhibitors that may provide therapeutic strategies to combat these human and livestock pathogens.

In ciliated protozoa another RNA-driven peculiarity has been identified. Here, chromatin diminution leads to the rearrangement of germline chromatin in somatic cells where chromosomal regions are excised and remaining DNA fragments are specifically rejoined. A paper from the Landweber¹⁴ group in this issue demonstrates that in this setting small and long non-coding RNAs are able to affect the chromatin state and drive and maintain chromosomal fusions in the ciliate Oxytricha.

Similarly, the chromatin state in most eukaryotes seems to be controlled by short non-coding RNAs large fractions of which are believed to be produced by pervasive transcription. Joan Steitz's¹⁵ laboratory has recently described stress induced pervasive readthrough transcription downstream of genes (DoG). In a point of view the biogenesis and mechanistic consequences on the maintenance of chromatin by these DoG transcripts is discussed.

Clearly, RNA sequencing has revolutionized our view on the complexity of the transcriptome and has provided significant insight in the transcriptomic changes during differentiation, organogenesis, or pathogenesis. However, the interconnection of many RNA processing, modification and turnover processes are not well understood, mainly because information at the single cell level is still missing. In an interesting review Simone Picelli¹⁶ describes recent advances and challenges in single cell sequencing.

It becomes increasingly evident from the publications presented in this Special Issue on RNA and Disease that many processes that affect the life and fate of an RNA can also be the underlying cause of diseases when disturbed. Consequently, it is logic that RNA could be a therapeutic target with several advantages over gene-therapy. A review by Thorsten Stafforst¹⁷ summarizes the current status and approaches to target RNAs therapeutically or to develop RNA as therapeutic agent a very promising field for drug development.

The power of basic research to uncover biologic mechanism and the persistence to follow these results in translational research was recently shown by the FDA approval for the first drug for spinal muscular atrophy (SMA) (FDA News Release, December 23, 2016). This splicing related disease was investigated by the group of Adrian Krainer at the Cold Spring Harbor Labs using a therapeutic anti-sense based splice-switching therapy.¹⁸ The astonishing demonstrations of improving this devastating disease highlight the potential of any basic scientific result to lead to a relieve or a cure of a disease.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

Work in the laboratories of Andrea Barta and Michael Jantsch is supported by FWF grants F43 and W1207.