Immune health maintained by meticulously ordered DNA

Walter and Eliza Hall Institute researchers have revealed how immune health is maintained by the exquisite organisation skills of a protein called Pax5.

The new study published today in Nature Immunology shows how Pax5 helps to efficiently organise the genetic information (DNA) required for our immune cells to maintain their form, function and help fight disease. The findings also suggest that a breakdown in this process of organisation by Pax5 could increase the risk of diseases such cancer.

The research was led by Dr. Rhys Allan and Dr. Tim Johanson, in collaboration with Professor Stephen Nutt and bioinformaticians Professor Gordon Smyth and Dr. Hannah Coughlan from the Walter and Eliza Hall Institute of Medical Research.

The importance of maintaining order

Dr. Johanson said the researchers had shown, for the first time, that Pax5 could sweep across the genome and fold, twist and store DNA for B cells in a fantastically ordered way—making each cell into a jam-packed but very neat suitcase.

“This immaculate organisation is crucial because each cell contains roughly two meters of DNA—that’s a huge amount of material to fit inside something smaller than a grain of sand.

“Every second of every day, different cells require access to highly specific parts of DNA in order to perform a myriad of jobs that help keep us healthy,” he said.

Dr. Johanson said life depended on cells accessing what they needed, when they needed it.

“For instance, immune B cells must access the right information to produce potentially life-saving antibodies that are critical for vaccine and immune responses.

“Think of how a meticulously ordered suitcase increases your chance of finding a specific item of clothing at a moment’s notice, and, how a jumbled case could work against you finding what you need. In the case of our bodies, the difference between order and disorder can be a matter of life and death,” he said.

Disorder leads to disease

Dr. Allan said the disarray of DNA could lead to errors ‘further down the line’.

“Seemingly small errors in the process of DNA organisation can turn out to be very serious drivers for disease.

“A lack of instructions required to function can put cells at risk of morphing or devolving into something they perhaps shouldn’t be—like a cancer cell. It is therefore unsurprising that Pax5 is faulty in many childhood leukaemias.”

The power of computing

Dr. Coughlan said recent technological advances had allowed the teams to visualise Pax5’s activity across the genome for the first time.

“With the help of powerful computers, we performed thousands of complex calculations to spot the difference in DNA organisation when Pax5 was present, versus absent, from the B cells. Our analyses showed that without Pax5, the cells could no longer package their DNA adequately.

“Bioinformatics is shining a light on how vital factors regulate our DNA. This in turns progresses an understanding of what could be going wrong in cases of disease,” she said.

Two roles for the same player

Dr. Allan said the findings were particularly intriguing because for two decades Pax5 was known only as a ‘transcription factor’.

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