PauparLncRNA Promotes KAP1 Dependent Chromatin Changes And Regulates Subventricular Zone Neurogenesis

Many long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet theirin vivoroles and molecular mechanisms of action remain poorly understood.Paupar, a CNS expressed lncRNA, controls neuroblastoma cell growth by binding and modulating the activity of genome-wide transcriptional regulatory elements. We show here thatPaupartranscript directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation.Pauparpromotes KAP1 chromatin occupancy and H3K9me3 deposition at a subset of distal targets, through formation of a DNA binding ribonucleoprotein complex containingPaupar, KAP1 and the PAX6 transcription factor.Paupar-KAP1 genome-wide co-occupancy reveals a 4-fold enrichment of overlap betweenPauparand KAP1 bound sequences. Furthermore, bothPauparand Kap1 loss of functionin vivoaccelerates lineage progression in the mouse postnatal subventricular zone (SVZ) stem cell niche and disrupts olfactory bulb neurogenesis. These observations provide important conceptual insights into thetrans-acting modes of lncRNA-mediated epigenetic regulation, the mechanisms of KAP1 genomic recruitment and identifyPauparandKap1as regulators of SVZ neurogenesis.