The long non‐coding <scp>RNA</scp> <i>Paupar</i> promotes <scp>KAP</scp> 1‐dependent chromatin changes and regulates olfactory bulb neurogenesis

Abstract

Many long non-coding RNAs (lncRNAs) are expressed during central nervous system (CNS) development, yet their <i>in vivo</i> roles and mechanisms of action remain poorly understood. <i>Paupar</i>, a CNS-expressed lncRNA, controls neuroblastoma cell growth by binding and modulating the activity of transcriptional regulatory elements in a genome-wide manner. We show here that the <i>Paupar</i> lncRNA directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation. <i>Paupar</i> promotes KAP1 chromatin occupancy and H3K9me3 deposition at a subset of distal targets, through the formation of a ribonucleoprotein complex containing <i>Paupar</i>, KAP1 and the PAX6 transcription factor. <i>Paupar</i>-KAP1 genome-wide co-occupancy reveals a fourfold enrichment of overlap between <i>Paupar</i> and KAP1 bound sequences, the majority of which also appear to associate with PAX6. Furthermore, both <i>Paupar</i> and <i>Kap1</i> loss-of-function <i>in vivo</i> disrupt olfactory bulb neurogenesis. These observations provide important conceptual insights into the <i>trans</i>-acting modes of lncRNA-mediated epigenetic regulation and the mechanisms of KAP1 genomic recruitment, and identify <i>Paupar</i> and <i>Kap1</i> as regulators of neurogenesis <i>in vivo</i>.