Unraveling the Mystery of Genes That Are Key to Brain Development

Summary: Study reveals the mechanism by which genes coding for a subset of long non-coding RNA interact with neighboring genes to regulate the development and function of cortical neurons.

Source: University of Bath

Scientists are starting to understand the precise workings of a type of gene that, unlike other genes, does not code for proteins – the building blocks of life.

New research led by the University of Bath shows the mechanism by which genes coding for a subset of long non-coding RNA (lncRNA) interact with neighbouring genes to regulate the development and function of essential nerve cells.

Despite their prevalence on genes coding for lncRNA in the genome (estimates range from 18,000-60,000 lncRNA genes in the human genome compared to 20,000 protein-coding genes), these segments of DNA were once written-off as junk precisely because the information contained within them does not result in the production of a protein.

However, it is now clear that some lncRNAs are anything but scrap, and these may come to play a key role in restoring physical function in people who have suffered serious nerve damage.

Although the function of most lncRNA genes remains a mystery, a subset are co-expressed in the brain along with neighboring genes that code for proteins involved in gene expression control. In other words, genes for these lncRNAs and their protein-coding neighbors work as a pair. Together, they regulate the development and function of essential nerve cells, particularly in the brain during embryonic development and in early life.

This shows cortical neurons
Differentiated cortical neurons expressing the axonal marker Tau (green) and the dendritic marker MAP-2 (red). Credit: Robert Williams, University of Bath

The new study describes the regulatory pathway involved in controlling the levels of one of these gene pairs. Their location and quantity in the genome need to be carefully coordinated, as does the timing of their activity.

“We previously defined one of the most profound functions for lncRNA in the brain and our new study identifies an important signaling pathway that acts to coordinate the expression of this lncRNA and the key protein coding gene that it is paired with,” explains Dr Keith Vance, lead author of the study from the Department of Biology & Biochemistry at Bath.

“This new research takes us closer to understanding the basic biology of nerve cells and how they are produced. Regenerative medicine is the end-game and with further research we hope to develop a deeper understanding of how lncRNA genes operate in the brain.”

He adds: “This knowledge could be important for scientists looking for ways to replace defective neurons and restore nerve function – for instance in people who have had strokes.”

Funding: The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and is published today in PLOS Genetics.

About this genetics and brain development research news

Author: Chris Melvin
Source: University of Bath
Contact: Chris Melvin – University of Bath
Image: The image is credited to Robert Williams, University of Bath

Original Research: Open access.
Chromatin interaction maps identify Wnt responsive cis-regulatory elements coordinating Paupar-Pax6 expression in neuronal cells” by Keith Vance et al. PLOS Genetics


Chromatin interaction maps identify Wnt responsive cis-regulatory elements coordinating Paupar-Pax6 expression in neuronal cells

Central nervous system-expressed long non-coding RNAs (lncRNAs) are often located in the genome close to protein coding genes involved in transcriptional control. Such lncRNA-protein coding gene pairs are frequently temporally and spatially co-expressed in the nervous system and are predicted to act together to regulate neuronal development and function.

Although some of these lncRNAs also bind and modulate the activity of the encoded transcription factors, the regulatory mechanisms controlling co-expression of neighbouring lncRNA-protein coding genes remain unclear.

Here, we used high resolution NG Capture-C to map the cis-regulatory interaction landscape of the key neuro-developmental Paupar-Pax6 lncRNA-mRNA locus.

The results define chromatin architecture changes associated with high PauparPax6 expression in neurons and identify both promoter selective as well as shared cis-regulatory-promoter interactions involved in regulating PauparPax6 co-expression.

We discovered that the TCF7L2 transcription factor, a regulator of chromatin architecture and major effector of the Wnt signalling pathway, binds to a subset of these candidate cis-regulatory elements to coordinate Paupar and Pax6 co-expression.

We describe distinct roles for Paupar in Pax6 expression control and show that the Paupar DNA locus contains a TCF7L2 bound transcriptional silencer whilst the Paupar transcript can act as an activator of Pax6.

Our work provides important insights into the chromatin interactions, signalling pathways and transcription factors controlling co-expression of adjacent lncRNAs and protein coding genes in the brain.

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