Chromatin interaction maps identify Wnt responsivecis-regulatory elements coordinatingPaupar-Pax6expression in neuronal cells

AbstractCentral nervous system-expressed long non-coding RNAs (lncRNAs) are often located in the genome close to protein coding genes involved in transcriptional control. Such lncRNA-protein coding gene pairs are frequently temporally and spatially co-expressed in the nervous system and are predicted to act together to regulate neuronal development and function. Although some of these lncRNAs also bind and modulate the activity of the encoded transcription factors, the regulatory mechanisms controlling co-expression of neighbouring lncRNA-protein coding genes remain unclear. Here, we used high resolution NG Capture-C to map thecis-regulatory interaction landscape of the key neuro-developmentalPaupar-Pax6lncRNA-mRNA locus. The results defined chromatin architecture changes associated with highPaupar-Pax6expression in neurons and identified both promoter selective as well as sharedcis-regulatory interactions with thePauparandPax6promoters involved in regulatingPaupar-Pax6co-expression in neuronal cells. The TCF7L2 transcription factor, a major regulator of chromatin architecture and effector of the Wnt signalling pathway, binds to a subset of these candidatecis-regulatory elements to coordinatePauparandPax6co-expression. We identify a functional TCF7L2 boundcis-regulatory element within thePaupargene, suggesting that thePauparDNA locus itself regulatesPax6expression in addition to its previously described transcriptdependent modes of action. Our work provides important insights into the chromatin interactions, signalling pathways and transcription factors controlling co-expression of adjacent lncRNAs and protein coding genes in the brain.