Summary: Researchers reveal a non-coding RNA called Paupar is critical in influencing healthy brain development.
Source: University of Bath.
New research has shown how an unusual gene is needed for brain development in young mice.
Since the human genome was first sequenced in 2001, scientists have puzzled over swathes of our DNA that despite apparently lacking function are made into ribonucleic acid (RNA) by the cell. Why make RNA at all when it is not then used to make proteins, which perform fundamental biological tasks? Perhaps these so-called non-coding RNAs perform critical, but as yet unknown, tasks?
Scientists from the Universities of Bath, Oxford and Edinburgh have now identified one such non-coding RNA, called Paupar, which influences how healthy brains develop during early life. They have shown that Paupar orchestrates proteins that control neurodevelopment.
They studied KAP1, a gene that codes for an essential protein associated with several fundamental processes in neurodevelopment. The KAP1 protein acts as a regulator for several other genes which allow the brain to grow healthily and develop several types of brain cell.
Using molecular biology techniques they discovered that Paupar can act as a switch, modulating how KAP1 acts by binding to it- thus influencing the development of healthy brains in mice. It is the first time that a non-coding RNA has been shown to bind to KAP1.
The research is published in The EMBO Journal.
Dr Keith Vance, from the University of Bath Department of Biology & Biochemistry led the research. He said: “It is now clear that the genome expresses many non-coding RNAs that are not made into protein. Despite this, there is a lot of controversy regarding their function. Some groups argue that these non-coding RNAs are a result of transcriptional noise with no apparent use whilst others think that the vast majority of them must be doing something important.
“We have shown here good evidence that one of these genes, called Paupar, is important for development of the brain.
“It’s a young field, but I think it’s clear we have to reassess the central dogma of molecular biology that DNA is transcribed to RNA that codes for a protein. We’re now seeing that some RNAs can go off and do something themselves.
“Our findings also help us understand the essential role of KAP1, which is something we’re really interested in as we look at the development of the central nervous system.”
Funding: This research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Medical Research Council (MRC).
Source: Chris Melvin – University of Bath
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Francis Szele.
Original Research: Open access research for “The long non‐coding RNA Paupar promotes KAP1‐dependent chromatin changes and regulates olfactory bulb neurogenesis” by Ioanna Pavlaki, Farah Alammari, Bin Sun, Neil Clark, Tamara Sirey, Sheena Lee, Dan J Woodcock, Chris P Ponting, Francis G Szele, and Keith W Vance in The EMBO Journal. Published April 16 2018.
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 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.