The Sox2 transcription factor binds RNA

Abstract

Certain transcription factors are proposed to form functional interactions with RNA to facilitate proper regulation of gene expression. Sox2, a transcription factor critical for maintenance of pluripotency and neurogenesis, has been found associated with several lncRNAs, although it is unknown whether these interactions are direct or via other proteins. Here we demonstrate that human Sox2 interacts directly with one of these lncRNAs with high affinity through its HMG DNA-binding domain in vitro. These interactions are primarily with double-stranded RNA in a non-sequence specific fashion, mediated by a similar but not identical interaction surface. We further determined that Sox2 directly binds RNA in mouse embryonic stem cells by UV-cross-linked immunoprecipitation of Sox2 and more than a thousand Sox2-RNA interactions in vivo were identified using fRIP-seq. Together, these data reveal that Sox2 employs a high-affinity/low-specificity paradigm for RNA binding in vitro and in vivo.

NMD is required for timely cell fate transitions by fine-tuning gene expression and controlling translation

“…This interaction with the pluripotency circuitry remains to be explored, but could provide a direct link between translation initiation and cell fate control. Such a function accords with recent reports of Sox2 binding to the translation initiation factor transporter Eif4enif1, and Sox2 binding to RNA in mouse ESCs 44,45 .…”

Functional characterization of SOX2 as an anticancer target

“…Structurally, SOX2 directly interacts with lncRNAs with high affinity through its HMG DNA-binding domain. 71 Interestingly, functional SOX2 gene is embedded in the third intron of a long multi-exon noncoding RNA gene, which is known as SOX2 overlapping transcript (SOX2OT) . 72 SOX2 and SOX2OT are co-expressed in ESCs and both are transcribed in the same orientation.…”

The molecular structure of long non-coding RNAs: emerging patterns and functional implications

“…Finally, secondary structure elements identified in lncRNAs may display analogies to other known nucleic acid motifs and thus give insights into lncRNA functions. For example, the lncRNA-E2which is involved in pluripotency maintenance in embryonic stem cellsdisplays similarity to a DNA segment recognized by the transcription factor Sox2 (Ng et al 2012;Holmes et al 2020). Indeed, this segment recognizes the Sox2 DNA-binding HMG domain, using a partially overlapping set of amino acids than that used to interact with DNA, so that the interaction of Sox2 with DNA or RNA is mutually exclusive (Holmes et al 2020).…”

“…For example, the lncRNA-E2which is involved in pluripotency maintenance in embryonic stem cellsdisplays similarity to a DNA segment recognized by the transcription factor Sox2 (Ng et al 2012;Holmes et al 2020). Indeed, this segment recognizes the Sox2 DNA-binding HMG domain, using a partially overlapping set of amino acids than that used to interact with DNA, so that the interaction of Sox2 with DNA or RNA is mutually exclusive (Holmes et al 2020). A similar lncRNA-protein interaction has been described for the recognition of steroid receptors (SRs) by human GAS5, which promotes the inhibition of the steroid-mediated transcriptional activity (Kino et al 2010).…”