The long non‐coding RNA Paupar promotes KAP1‐dependent chromatin changes and regulates olfactory bulb neurogenesis

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...

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Vydáno v:	The EMBO journal Ročník 37; číslo 10
Hlavní autoři:	Pavlaki, Ioanna, Alammari, Farah, Sun, Bin, Clark, Neil, Sirey, Tamara, Lee, Sheena, Woodcock, Dan J, Ponting, Chris P, Szele, Francis G, Vance, Keith W
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 15.05.2018 Springer Nature B.V John Wiley and Sons Inc
Témata:	Animals Animals, Newborn Cell Cycle Cell Proliferation Cells, Cultured Central nervous system Chromatin Chromatin - genetics Deposition EMBO09 EMBO27 EMBO36 Epigenesis, Genetic Epigenetics Gene expression gene regulation Genes Genomes Genomics KAP1 lncRNA Mice Neural Stem Cells - cytology Neural Stem Cells - metabolism Neuroblastoma Neuroblastoma - genetics Neuroblastoma - metabolism Neuroblastoma - pathology Neurogenesis Non-coding RNA Olfaction Olfactory bulb Olfactory Bulb - cytology Olfactory Bulb - metabolism Pax6 protein PAX6 Transcription Factor - genetics PAX6 Transcription Factor - metabolism Proteins Regulators Regulatory Elements, Transcriptional Regulatory sequences Ribonucleic acid RNA RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism Transcription factors Tripartite Motif-Containing Protein 28 - genetics Tripartite Motif-Containing Protein 28 - metabolism neurogenesis lncRNA KAP1 chromatin gene regulation
ISSN:	0261-4189, 1460-2075, 1460-2075
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Shrnutí:	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 . Synopsis The formation of an RNP complex containing a long non‐coding RNA (lncRNA), a chromatin regulator and transcription factor illustrates how a single nuclear lncRNA can regulate transcription of multiple target genes in trans . The CNS‐expressed lncRNA Paupar interacts with the TRIM28/TIF1/KAP1 chromatin regulatory protein. Paupar acts in trans to promote KAP1 chromatin occupancy and H3K9me3 deposition at a subset of bound target sites. Paupar regulation in trans requires the formation of a ribonucleoprotein complex containing Paupar , KAP1 and non‐KRAB‐ZNF transcription factors such as PAX6. Paupar and KAP1 function as regulators of olfactory bulb neurogenesis in vivo . Graphical Abstract Complex formation between a long non‐coding RNA (lncRNA), a chromatin regulator and transcription factor illustrates how nuclear lncRNAs can regulate transcription in trans .
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.15252/embj.201798219