A new map reveals how immune system genes interact and regulate each other, underscoring the complexity of the immune system and unravelling possibly novel therapeutic targets.
Researchers in California were looking at genes involved in autoimmune diseases such as psoriasis, rheumatoid arthritis, and celiac disease. The effect of a known misfunctioning gene can be assessed by measuring its protein product and the known molecules affected by it – this is called a 'downstream approach' as it looks at interactions after the gene is transcribed. To unravel how immune genes are regulated, the researchers used an 'upstream' approach, disrupting the proteins called transcription factors that switch genes on and off, and observing the results.
'We really wanted to look at what is controlling key immune genes' said first author Dr Jacob Freimer from Stanford School of Medicine. 'This kind of upstream approach hadn't been done before in primary human cells… This let us go through over a thousand transcription factors and see which ones have an impact on these immune genes'.
Using a novel technique combining CRISPR and lentiviral RNA with Cas9 in human immune cells, they were able to discover 117 transcription factors regulating the expression of three immune factor genes: IL2RA, IL-2 and CTLA4. Then, they mapped where those regulators had an effect, and how they were themselves regulated.
The authors suggest their strategy to map gene networks could be useful to other fields besides immunology, uncovering previously unknown regulatory genes, and ultimately leading to increased understanding of diseases.
Co-senior author Dr Alex Marson from the University of California San Francisco said: 'When we understand the ways in which these networks and pathways are connected, it starts to help us understand key collections of genes that need to function properly to prevent diseases.'
The findings were published in Nature Genetics.