The long non‐coding RNA Paupar promotes KAP 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 in vivo roles and mechanisms of action remain poorly understood. Paupar, 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 Paupar lncRNA directly binds KAP1, an essential epigenetic regulatory protein, and thereby regulates the expression of shared target genes important for proliferation and neuronal differentiation. Paupar promotes KAP1 chromatin occupancy and H3K9me3 deposition at a subset of distal targets, through the formation of a ribonucleoprotein complex containing Paupar, KAP1 and the PAX6 transcription factor. Paupar‐KAP1 genome‐wide co‐occupancy reveals a fourfold enrichment of overlap between Paupar and KAP1 bound sequences, the majority of which also appear to associate with PAX6. Furthermore, both Paupar and Kap1 loss‐of‐function in vivo disrupt olfactory bulb neurogenesis. These observations provide important conceptual insights into the trans‐acting modes of lncRNA‐mediated epigenetic regulation and the mechanisms of KAP1 genomic recruitment, and identify Paupar and Kap1 as regulators of neurogenesis in vivo.

The MITF-SOX10 regulated long non-coding RNA DIRC3 is a melanoma tumour suppressor

“…In addition, a small number of lncRNA transcripts have been shown to act in trans by moving away from their sites of synthesis to bind and directly regulate multiple target genes on different chromosomes (7)(8)(9).…”

Interpreting the impact of noncoding structural variation in neurodevelopmental disorders

“…Although being transcribed divergently from the Pou3f2 locus, it works via a trans mechanism. Dlx1as and Six3os both play a role in glial-neuronal lineage specification of neural stem cells 25 , while Paupar regulates olfactory bulb neurogenesis 26 . Kleaveland et al even described a regulatory network in which a lncRNA (Cyrano), a circular RNA (Cdr1as), and two miRNAs (miR-7 and miR-671) work together to regulate neuronal activity 27 .…”

The functions of long non-coding RNAs in neural stem cell proliferation and differentiation

“…In addition, lncRNA Kdm2b divergently transcribed from the same promoter bidirectional with Kdm2b and dispersed chromatin environment via binding hnRNPAB, then activated its nearby coding gene-Kdm2b expression for facilitating neuronal differentiation in early neurogenesis cortical projection neurons [57]. LncRNA Paupar divergently transcription from upstream of Pax6 participates in regulation of neural differentiation and OB neurogenesis via binding with local genes-Pax6 and KAP1 in cis-manner, as well as modulation the activity of various transcriptional regulatory elements on different chromosomes distinguishing from its synthesis locus and alteration of chromatin occupancy and H3K9me3 deposition [58,59].…”