Dual personalities visualized for shape-shifting molecule

May 06, 2020

Australian and US researchers have made a breakthrough in understanding the structure of a key genetic molecule, called RNA, and revealing for the first time how these changes impact RNA's function.

Publishing in the journal Nature, the research team developed a bioinformatics technique to resolve separate structures of RNA rather than viewing them as a 'blur' that averaged multiple structures. This underpinned their discovery that the structure of RNA can influence how cells function.

RNA is a DNA-like molecule that encodes genetic information. Certain viruses - including HIV and SARS-CoV2 - use RNA as their genetic material. The team were able to apply the techniques they developed to reveal how the structure of HIV's RNA genome influences which proteins the virus produces.

The international collaborative team was led by Walter and Eliza Hall Institute researcher Dr Vincent Corbin together with Mr Phil Tomezsko and Professor Silvi Rouskin at the Whitehead Institute for Biomedical Research, Boston (US). The research team also included the Institute's Computational Biology Theme Leader Professor Tony Papenfuss and mathematician and PhD student Mr Lachlan McIntosh.

At a glanceRNA's shifting shapes

RNA is a molecule found in all living things that carries genetic information. RNA is an important regulator of how cells function, directly controlling which proteins are produced in cells, and can also switch genes on and off.

RNA molecules have a two-dimensional structure which influences how the genetic information contained within them can be accessed, said Dr Corbin, who led the project's bioinformatics research.

"The big question in RNA biology has been whether RNA molecules have a single, constant structure, or whether they can shift between different structures - and what this means for the function of a particular RNA molecule," he said.

"Our collaborators, led by Professor Silvi Rouskin, developed a technique for deciphering the structure of RNA molecules. We wanted to understand whether what we were detecting was a single structure of RNA, or an 'average' structure that blurs multiple different structures together.

"It's a bit like seeing red and yellow stripes, or blurring them together and thinking you can see orange," he said.

By developing a computational algorithm, the team were able to detect and measure the amount of different RNA structures. "We could detect these both in a test tube and in living cells, so we next looked at whether these structures influenced how RNA functioned," Dr Corbin said.

Changing RNA function

When RNA is produced in cells, it starts in a longer form that is 'spliced' or trimmed to remove unwanted parts.

"RNA splicing can influence how it encodes proteins," Dr Corbin said. "There are many examples of how altered RNA splicing influences how a cell functions - and in some cases, changes in RNA splicing have been associated with cancer or neurodegenerative diseases."

Certain viruses use RNA for their genome, including HIV and SARS-CoV2 (the coronavirus that causes COVID-19). In the case of HIV, RNA splicing influences which protein the virus produces - which changes at different stages of the virus's lifecycle.

"Using the HIV genome as a model system, we looked at whether RNA structure influences how HIV's RNA is spliced. We discovered that RNA structure was a critical determinant of RNA splicing in HIV, and influenced which viral proteins were produced," Dr Corbin said.

"This is the first clear evidence of how RNA structure can control RNA function. The techniques we have developed have opened up a new field of research into the role of RNA structure in regulating the function of cells."

Professor Papenfuss said the research showed how finely tuned biological systems are. "This study how very subtle changes in one tiny molecule can have big implications for the function of a virus. By using computational biology to unravel these changes, we've made a significant discovery about how viruses - and potentially human cells - function, which may underpin future discoveries about health and disease."
-end-
The research was supported by the US National Institutes of Health, the Smith Family Foundation, the Burroughs Wellcome Fund, the Australian National Health and Medical Research Council and the Victorian Government.

Walter and Eliza Hall Institute

Related HIV Articles from Brightsurf:

BEAT-HIV Delaney collaboratory issues recommendations measuring persistent HIV reservoirs
Spearheaded by Wistar scientists, top worldwide HIV researchers from the BEAT-HIV Martin Delaney Collaboratory to Cure HIV-1 Infection by Combination Immunotherapy (BEAT-HIV Collaboratory) compiled the first comprehensive set of recommendations on how to best measure the size of persistent HIV reservoirs during cure-directed clinical studies.

The Lancet HIV: Study suggests a second patient has been cured of HIV
A study of the second HIV patient to undergo successful stem cell transplantation from donors with a HIV-resistant gene, finds that there was no active viral infection in the patient's blood 30 months after they stopped anti-retroviral therapy, according to a case report published in The Lancet HIV journal and presented at CROI (Conference on Retroviruses and Opportunistic Infections).

Children with HIV score below HIV-negative peers in cognitive, motor function tests
Children who acquired HIV in utero or during birth or breastfeeding did not perform as well as their peers who do not have HIV on tests measuring cognitive ability, motor function and attention, according to a report published online today in Clinical Infectious Diseases.

Efforts to end the HIV epidemic must not ignore people already living with HIV
Efforts to prevent new HIV transmissions in the US must be accompanied by addressing HIV-associated comorbidities to improve the health of people already living with HIV, NIH experts assert in the third of a series of JAMA commentaries.

The Lancet HIV: Severe anti-LGBT legislations associated with lower testing and awareness of HIV in African countries
This first systematic review to investigate HIV testing, treatment and viral suppression in men who have sex with men in Africa finds that among the most recent studies (conducted after 2011) only half of men have been tested for HIV in the past 12 months.

The Lancet HIV: Tenfold increase in number of adolescents on HIV treatment in South Africa since 2010, but many still untreated
A new study of more than 700,000 one to 19-year olds being treated for HIV infection suggests a ten-fold increase in the number of adolescents aged 15 to 19 receiving HIV treatment in South Africa, according to results published in The Lancet HIV journal.

Starting HIV treatment in ERs may be key to ending HIV spread worldwide
In a follow-up study conducted in South Africa, Johns Hopkins Medicine researchers say they have evidence that hospital emergency departments (EDs) worldwide may be key strategic settings for curbing the spread of HIV infections in hard-to-reach populations if the EDs jump-start treatment and case management as well as diagnosis of the disease.

NIH HIV experts prioritize research to achieve sustained ART-free HIV remission
Achieving sustained remission of HIV without life-long antiretroviral therapy (ART) is a top HIV research priority, according to a new commentary in JAMA by experts at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

The Lancet HIV: PrEP implementation is associated with a rapid decline in new HIV infections
Study from Australia is the first to evaluate a population-level roll-out of pre-exposure prophylaxis (PrEP) in men who have sex with men.

Researchers date 'hibernating' HIV strains, advancing BC's leadership in HIV cure research
Researchers have developed a novel way for dating 'hibernating' HIV strains, in an advancement for HIV cure research.

Read More: HIV News and HIV Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.