Long Intergenic Non-Coding RNAs in HNSCC: From “Junk DNA” to Important Prognostic Factor

Head and neck squamous cell carcinoma is one of the most common and fatal cancers worldwide. Even a multimodal approach consisting of standard chemo- and radiotherapy along with surgical resection is only effective in approximately 50% of the cases. The rest of the patients develop a relapse of the disease and acquire resistance to treatment. Especially this group of individuals needs novel, personalized, targeted therapy. The first step to discovering such solutions is to investigate the tumor microenvironment, thus understanding the role and mechanism of the function of coding and non-coding sequences of the human genome. In recent years, RNA molecules gained great interest when the complex character of their impact on our biology allowed them to come out of the shadows of the “junk DNA” label. Furthermore, long non-coding RNAs (lncRNA), specifically the intergenic subgroup (lincRNA), are one of the most aberrantly expressed in several malignancies, which makes them particularly promising future diagnostic biomarkers and therapeutic targets. This review contains characteristics of known and validated lincRNAs in HNSCC, such as XIST, MALAT, HOTAIR, HOTTIP, lincRNA-p21, LINC02487, LINC02195, LINC00668, LINC00519, LINC00511, LINC00460, LINC00312, and LINC00052, with a description of their prognostic abilities. Even though much work remains to be done, lincRNAs are important factors in cancer biology that will become valuable biomarkers of tumor stage, outcome prognosis, and contribution to personalized medicine.

Nanopore RNA Sequencing Revealed Long Non-Coding and LTR Retrotransposon-Related RNAs Expressed at Early Stages of Triticale SEED Development

The intergenic space of plant genomes encodes many functionally important yet unexplored RNAs. The genomic loci encoding these RNAs are often considered “junk”, DNA as they are frequently associated with repeat-rich regions of the genome. The latter makes the annotations of these loci and the assembly of the corresponding transcripts using short RNAseq reads particularly challenging. Here, using long-read Nanopore direct RNA sequencing, we aimed to identify these “junk” RNA molecules, including long non-coding RNAs (lncRNAs) and transposon-derived transcripts expressed during early stages (10 days post anthesis) of seed development of triticale (AABBRR, 2n = 6x = 42), an interspecific hybrid between wheat and rye. Altogether, we found 796 lncRNAs and 20 LTR retrotransposon-related transcripts (RTE-RNAs) expressed at this stage, with most of them being previously unannotated and located in the intergenic as well as intronic regions. Sequence analysis of the lncRNAs provide evidence for the frequent exonization of Class I (retrotransposons) and class II (DNA transposons) transposon sequences and suggest direct influence of “junk” DNA on the structure and origin of lncRNAs. We show that the expression patterns of lncRNAs and RTE-related transcripts have high stage specificity. In turn, almost half of the lncRNAs located in Genomes A and B have the highest expression levels at 10–30 days post anthesis in wheat. Detailed analysis of the protein-coding potential of the RTE-RNAs showed that 75% of them carry open reading frames (ORFs) for a diverse set of GAG proteins, the main component of virus-like particles of LTR retrotransposons. We further experimentally demonstrated that some RTE-RNAs originate from autonomous LTR retrotransposons with ongoing transposition activity during early stages of triticale seed development. Overall, our results provide a framework for further exploration of the newly discovered lncRNAs and RTE-RNAs in functional and genome-wide association studies in triticale and wheat. Our study also demonstrates that Nanopore direct RNA sequencing is an indispensable tool for the elucidation of lncRNA and retrotransposon transcripts.

Regeneration: Why junk DNA might matter

The ability of certain natural species to restore or regenerate missing structures has been a recurrent source of inspiration to forge our collective knowledge, from being used to adorn mythological figures with superhuman powers to permitting controlled reproducible observations that help setting the bases of entire research fields such as experimental biology and regenerative medicine. In spite of being one of the oldest natural phenomena under study, what makes certain species able or unable to regenerate missing parts is still largely a mystery. Recent advancements towards the highly detailed characterization of the sequence, the spatial organization, and the expression of genomes is offering a new standpoint to address the study of the natural variation in regenerative responses. An intriguing observation that has not yet conveniently pursued is that species with remarkable regenerative abilities tend to have genomes loaded with junk DNA (jDNA), i.e., genetic elements presumed to be useless for the benefit of the individual, whereas species for taxa with limited regenerative abilities tend to have jDNA-poor genomes. Here, I use existing knowledge on the role of jDNA as genome evolution facilitator and its non-random chromosome and nuclear distributions to speculate about two non-excluding ways through which the variation in jDNA genomic content might end up enhancing or limiting regenerative responses. The present piece aims to go beyond the confines of correlational studies between biological variables and to lay sensible conceptual grounds for future hypothesis-driven attempts to substantiate the genomic determinants of the natural variation of regenerative responses.

Regeneration: Why junk DNA might matter

The ability of certain natural species to restore or regenerate missing structures has been a recurrent source of inspiration to forge our collective knowledge, from being used to adorn mythological figures with superhuman powers to permitting controlled reproducible observations that help setting the bases of entire research fields such as experimental biology and regenerative medicine. In spite of being one of the oldest natural phenomena under study, what makes certain species able or unable to regenerate missing parts is still largely a mystery. Recent advancements towards the highly detailed characterization of the sequence, the spatial organization, and the expression of genomes is offering a new standpoint to address the study of the natural variation in regenerative responses. An intriguing observation that has not yet conveniently pursued is that species with remarkable regenerative abilities tend to have genomes loaded with junk DNA (jDNA), i.e., genetic elements presumed to be useless for the benefit of the individual, whereas species for taxa with limited regenerative abilities tend to have jDNA-poor genomes. Here, I use existing knowledge on the role of jDNA as genome evolution facilitator and its non-random chromosome and nuclear distributions to speculate about two non-excluding ways through which the variation in jDNA genomic content might end up enhancing or limiting regenerative responses. The present piece aims to go beyond the confines of correlational studies between biological variables and to lay sensible conceptual grounds for future hypothesis-driven attempts to substantiate the genomic determinants of the natural variation of regenerative responses.

Origin of biomolecular games: deception and molecular evolution

Biological macromolecules encode information: some of it to endow the molecule with structural flexibility, some of it to enable molecular actions as a catalyst or a substrate, but a residual part can be used to communicate with other macromolecules. Thus, macromolecules do not need to possess information only to survive in an environment, but also to strategically interact with others by sending signals to a receiving macromolecule that can properly interpret the signal and act suitably. These sender–receiver signalling games are sustained by the information asymmetry that exists among the macromolecules. In both biochemistry and molecular evolution, the important role of information asymmetry remains largely unaddressed. Here, we provide a new unifying perspective on the impact of information symmetry between macromolecules on molecular evolutionary processes, while focusing on molecular deception. Biomolecular games arise from the ability of biological macromolecules to exert precise recognition, and their role as units of selection, meaning that they are subject to competition and cooperation with other macromolecules. Thus, signalling game theory can be used to better understand fundamental features of living systems such as molecular recognition, molecular mimicry, selfish elements and ‘junk’ DNA. We show how deceptive behaviour at the molecular level indicates a conflict of interest, and so provides evidence of genetic conflict. This model proposes that molecular deception is diagnostic of selfish behaviour, helping to explain the evasive behaviour of transposable elements in ‘junk’ DNA, for example. Additionally, in this broad review, a range of major evolutionary transitions are shown to be associated with the establishment of signalling conventions, many of which are susceptible to molecular deception. These perspectives allow us to assign rudimentary behaviour to macromolecules, and show how participation in signalling games differentiates biochemistry from abiotic chemistry.