Regulation potential of transcribed simple repeated sequences in developing neurons

Abstract

Simple repeated sequences (SRSs), defined as tandem iterations of microsatellite- to satellite-sized DNA units, occupy a substantial part of the human genome. Some of these elements are known to be transcribed in the context of repeat expansion disorders. Mounting evidence suggests that the transcription of SRSs may also contribute to normal cellular functions. Here, we used genome-wide bioinformatics approaches to systematically examine SRS transcriptional activity in cells undergoing neuronal differentiation. We identified thousands of long noncoding RNAs containing >200-nucleotide-long SRSs (SRS-lncRNAs), with hundreds of these transcripts significantly upregulated in the neural lineage. We show that SRS-lncRNAs often originate from telomere-proximal regions and that they have a strong potential to form multivalent contacts with a wide range of RNA-binding proteins. Our analyses also uncovered a cluster of neurally upregulated SRS-lncRNAs encoded in a centromere-proximal part of chromosome 9, which underwent an evolutionarily recent segmental duplication. Using a newly established in vitro system for rapid neuronal differentiation of induced pluripotent stem cells, we demonstrate that at least some of the bioinformatically predicted SRS-lncRNAs, including those encoded in the segmentally duplicated part of chromosome 9, indeed increase their expression in developing neurons to readily detectable levels. These data suggest that many SRSs may be expressed in a cell type and developmental stage-specific manner, providing a valuable resource for further studies focused on the functional consequences of SRS-lncRNAs in the normal development of the human brain.

Identifying inversions with Breakpoints in the Dystrophin Gene through Long-Read Sequencing: Report of Two Cases

“…A variety of repetitive sequences have been identi ed as drivers for aberrant recombination events within the genome, which result in the formation of structural variants, including inversions [25,26]. Traditionally, repeated DNA sequences have been categorized as either interspersed or tandem repeats, distinguished by their respective positions and the mechanisms driving their expansion [27]. In previous reports concerning intrachromosomal inversions in patients with DMD, the breakpoints were predominantly located within interspersed repeats [2,12,14].…”

“…In previous reports concerning intrachromosomal inversions in patients with DMD, the breakpoints were predominantly located within interspersed repeats [2,12,14]. Simple repeated sequences (SRS) are de ned as tandem repeats of microsatellite-sized (≤ 9bp units), minisatellite-sized (10-60bp units), or satellite-sized (> 60bp units) DNA sequences [27]. In the rst case, (TA)n repeat sequences are located at the breakpoint, while in the second case, (CATATA)n repeat sequences are present at the breakpoint.…”