Abstract
Transposable elements (TEs), which cover ~45% of the human genome, although firstly considered as “selfish” DNA, are nowadays recognized as driving forces in eukaryotic genome evolution. This capability resides in generating a plethora of sophisticated RNA regulatory networks that influence the cell type specific transcriptome in health and disease. Indeed, TEs are transcribed and their RNAs mediate multi-layered transcriptional regulatory functions in cellular identity establishment, but also in the regulation of cellular plasticity and adaptability to environmental cues, as occurs in the immune response. Moreover, TEs transcriptional deregulation also evolved to promote pathogenesis, as in autoimmune and inflammatory diseases and cancers. Importantly, many of these findings have been achieved through the employment of Next Generation Sequencing (NGS) technologies and bioinformatic tools that are in continuous improvement to overcome the limitations of analyzing TEs sequences. However, they are highly homologous, and their annotation is still ambiguous. Here, we will review some of the most recent findings, questions and improvements to study at high resolution this intriguing portion of the human genome in health and diseases, opening the scenario to novel therapeutic opportunities.
Highlights
International decade-long projects such as ENCODE (Encyclopedia of DNA Elements) and FANTOM (Functional Annotation of the Mammalian Genome) have produced and bioinformatically analyzed a vast number of datasets opening the way for studying Transposable Elements (TEs). These results revealed that TEs have precise functions in establishing and influencing the cell type specific transcriptional programs, creating regulatory networks that are fostered both by their genomic elements and the derived transcripts [3,28], revealing that the RNAs transcribed from this elements could have a myriad of functions, definitely changing the way in which many genomic concepts were written in textbooks [29]
Faulkner et al [145] showed a method to recover short multi-reads produced by tag-based Next Generation Sequencing (NGS) technologies such as cap analysis of gene expression (CAGE), in which a score is given to tag-transcription start sites (TSS) associations according to the amount of individual tags associated to the same TSS; multi-mapping tags are proportionally assigned to the mapped TSS according to the calculated scores
We summarized the latest findings on TEs, highlighting that, beyond their ability of being “jumping elements”, they contribute to the establishment of a vast regulatory network that, controlling genome plasticity, magnifies the cell type specific transcriptional complexity, both in health and diseases
Summary
The hosts have developed many systems to control TEs expression and expansion [24] (epigenetic modification and noncoding RNAs (ncRNA) such Piwi interacting-RNAs) to contain the possible detrimental effects of their retrotransposition This expansion has achieved a balance between detrimental and beneficial effects, possibly becoming a novel regulatory mechanism to promote genomic functions acquired through evolution [3]. It is nowadays accepted, both in mouse and in human, that TEs have been co-opted into multiple regulatory functions for the accommodation of the host genomes metabolisms and transcription, mediated both by their DNA elements and by their transcribed RNAs counterparts
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