Complex architecture and regulated expression of the Sox2ot locus during vertebrate development

Abstract

The Sox2 gene is a key regulator of pluripotency embedded within an intron of a long noncoding RNA (ncRNA), termed Sox2 overlapping transcript (Sox2ot), which is transcribed in the same orientation. However, this ncRNA remains uncharacterized. Here we show that Sox2ot has multiple transcription start sites associated with genomic features that indicate regulated expression, including highly conserved elements (HCEs) and chromatin marks characteristic of gene promoters. To identify biological processes in which Sox2ot may be involved, we analyzed its expression in several developmental systems, compared to expression of Sox2. We show that Sox2ot is a stable transcript expressed in mouse embryonic stem cells, which, like Sox2, is down-regulated upon induction of embryoid body (EB) differentiation. However, in contrast to Sox2, Sox2ot is up-regulated during EB mesoderm-lineage differentiation. In adult mouse, Sox2ot isoforms were detected in tissues where Sox2 is expressed, as well as in different tissues, supporting independent regulation of expression of the ncRNA. Sox2dot, an isoform of Sox2ot transcribed from a distal HCE located >500 kb upstream of Sox2, was detected exclusively in the mouse brain, with enrichment in regions of adult neurogenesis. In addition, Sox2ot isoforms are transcribed from HCEs upstream of Sox2 in other vertebrates, including in several regions of the human brain. We also show that Sox2ot is dynamically regulated during chicken and zebrafish embryogenesis, consistently associated with central nervous system structures. These observations provide insight into the structure and regulation of the Sox2ot gene, and suggest conserved roles for Sox2ot orthologs during vertebrate development.

Two Novel Splice Variants of SOX2OT, SOX2OT-S1, and SOX2OT-S2 are Coupregulated with SOX2 and OCT4 in Esophageal Squamous Cell Carcinoma

“…SOX2 is an intronless gene that lies within the third intron of another gene known as SOX2OT [28]. SOX2OT has been proposed to function in the transcriptional regulation of SOX2 [29]. However, its exact biological function has yet remained elusive.…”

“…Recently, in order to identify the biological roles of sox2ot, Amaral et al [29] analyzed the expression pattern of this lncRNA in several developmental systems, in comparison to the expression of sox2. These analyses revealed that sox2ot, similar to sox2, is expressed in mouse ESCs.…”

Long non-coding RNA SOX2OT promotes cell proliferation and motility in human ovarian cancer

“…The concurrent expression pattern between lncRNA, SOX2OT and SOX2 in certain types of human cancer and human stem cells indicates the possibility that they may be involved in specific similar signaling pathways and engage in co-regulation, which has been validated by some recent studies (15)(16)(17). SOX2OT was postulated to participate in SOX2 transcription, acting as an important enhancer (14). Functionally, the lncRNA, SOX2OT, has a significant role in tumorigenesis.…”

“…SOX2OT is an evolutionarily conserved gene that has a high degree of nucleotide identity, with its homologues in mice and other vertebrates (12). The gene does not contain open reading frames, however, it is spliced into several transcripts that are microRNA-like (14). The concurrent expression pattern between lncRNA, SOX2OT and SOX2 in certain types of human cancer and human stem cells indicates the possibility that they may be involved in specific similar signaling pathways and engage in co-regulation, which has been validated by some recent studies (15)(16)(17).…”

Improved definition of the mouse transcriptome via targeted RNA sequencing

“…Recently, there has been increasing evidence that lncRNAs serve crucial biological roles (Mattick 2009). Examples include organism development (Amaral et al 2009;Mattick 2011), imprinting (Zhang et al 2014), epigenetic control (Nakagawa and Kageyama 2014), X inactivation (Froberg et al 2013), and cancer etiology (Yang et al 2014). …”