Sox2- lncRNA-mediated mechanisms of chromosome topological control in developing forebrain.

The long non-coding RNA directs ultraconserved enhancer()-intrachromosomal interactions, regulating genes across a 27 Mb region on chromosome 6 in mouse developing forebrain. Here, we show that long-range gene repression occurs through multi-step mechanisms involving the transcription factor Sox2. directly interacts with Sox2, antagonizing Sox2 activation of , and recruits Sox2 to the shadow enhancer and key interaction sites. Sox2 directly interacts with Dlx1 and Smarca4, as part of the ribonucleoprotein complex, forming spherical subnuclear domains (protein pools, PPs). targets Sox2 PPs to one long-range repressed target gene (), at the expense of another () and Sox2 shift interactions towards , linking /Sox2 co-regulated topological control and gene repression. We propose a model that distinguishes gene repression mechanisms at Rbm28 ( position) and Akr1b8 (limited Sox2 availability). Genome-wide control of RNPs (Sox2, Dlx and Smarca4) shows that co-recruitment influences Sox2 DNA binding. Together, these data suggest that organizes a Sox2 PP subnuclear domain and, through Sox2-RNP sequestration and recruitment, regulates chromosome 6 long-range targeting and activity with genome-wide consequences.