The long non-coding RNA Paupar promotes KAP1-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.

• Authors: Ioanna Pavlaki, Farah Alammari, Bin Sun, Neil Clark, Tamara Sirey, Sheena Lee, Dan J Woodcock, Chris P Ponting, Francis G Szele, Keith W Vance
• Journal: The EMBO journal (EMBO J) Vol. 37 Issue 10 (05 15 2018) ISSN: 1460-2075 [Electronic] England
• PMID: 29661885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• Chromatin
• PAX6 Transcription Factor
• Paupar long-non-coding RNA, mouse
• Pax6 protein, mouse
• RNA, Long Noncoding
• Trim28 protein, mouse
• Tripartite Motif-Containing Protein 28

Topics

• Animals
• Animals, Newborn
• Cell Cycle
• Cell Proliferation
• Cells, Cultured
• Chromatin (genetics)
• Epigenesis, Genetic
• Genomics
• Mice
• Neural Stem Cells (cytology, metabolism)
• Neuroblastoma (genetics, metabolism, pathology)
• Neurogenesis
• Olfactory Bulb (cytology, metabolism)
• PAX6 Transcription Factor (genetics, metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• Regulatory Elements, Transcriptional
• Tripartite Motif-Containing Protein 28 (genetics, metabolism)