Regulation Potential of Transcribed Simple Repeated Sequences in Developing Neurons

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 and other lines of evidence 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, as well as in the context of neurodevelopmental disorders.