Rogers receives NIH grant to study molecular processes that affect gene regulation

Thursday, Nov 21, 2024 • Greg Pederson :

Alicia Rogers, UTA assistant professor of biology

A biologist at The University of Texas at Arlington is leading a federally funded project to study the molecular processes that affect gene regulation with the long-term goal of advancing our understanding of how small RNA pathways impact human health and developing synthetic gene therapies to treat or prevent diseases, such as cancer.

Alicia Rogers, assistant professor of biology, received a five-year, $1.8 million grant from the National Institutes of Health (NIH) – National Institute of General Medical Sciences for the project, which is titled “Understanding what regulates a regulator: the molecular basis for homeostatic small RNA-mediated gene regulation”.

Rogers also recently co-authored a paper on small RNA pathway function which was published in the journal Nucleic Acids Research. The paper, titled “Small RNA-mediated genetic switches coordinate ALG-3/4 small RNA pathway function,” was written with Trilotma Sen, a doctoral student in Rogers’ lab, and Cara McCormick, a former research technician in her lab.

NIH grant project
Ribonucleic acid (RNA) is found in all living cells and there are several different types. RNAs are involved in protein synthesis, which is the process of turning genetic instructions into proteins in cells. While some RNAs provide the template for protein sequences, other non-coding RNAs are involved in regulating gene expression, which in turn affects many biological processes.

RNA interference (RNAi) describes a cellular mechanism that uses small RNAs complementary to the gene’s own DNA sequence to regulate the gene, a process that scientists call silencing.

“Defects in RNAi cause devastating gene dysregulation and allows de-repressed transposons to wreak havoc on the genome, resulting in the onset of cancers, infertility, neurodegenerative disorders, and many other diseases,” Rogers said. “Therefore, it is critical we learn how balancing between the interdependent RNAi pathways is maintained, and how RNAi homeostasis is impacted by real-world stresses, to advance our understanding of small RNAs in human health and disease.”

The NIH project’s focus is to study how small RNA pathways regulate genes properly and protect them from stressors. Rogers, Sen, and doctoral student Ha Meem hope to gain a fundamental understanding of this process with the long-term goal of harnessing that knowledge to find ways to prevent and treat diseases in humans.

They will carry out their research using a microscopic worm, C. elegans, as their model system. One reason they selected C. elegans is because it was in this small nematode where small RNA pathways were first discovered. Small ENA pathway discoveries in C. elegans have resulted in two Nobel Prize awards, in 2006 (Andrew Fire and Craig Mello) and 2024 (Victor Ambros and Gary Ruvkun).

“It’s a beautiful model system where we have a lot of genetic control,” Rogers said. “The animal is transparent so we can image things and use microscopy as one way to study these pathways in conjunction with molecular biology and genetics. Even though it’s a microscopic worm, because these pathways are evolutionarily conserved, the principles that we’re going to hopefully uncover in the worm will be applicable to the way that the pathways work in humans.”

The team has three main areas of emphasis in the study: the mechanisms of target transcript sorting among distinct RNAi branches; how RNAi pathways are temporally regulated throughout development; and the molecular and physiological consequences of disrupting RNAi homeostasis.

“Addressing these fundamental questions is critical for our understanding of small RNAs in human health and is important for the development of bioengineering techniques that harness the power of our own regulatory networks for use in therapeutic synthetic gene regulation,” Rogers said.

 

Nucleic Acids Research paper

The publication in Nucleic Acids Research provided the preliminary data on which the NIH grant is based. Rogers and her students examined the process of spermatogenesis in C. elegans and how small RNA pathways regulate themselves in order to maintain pathway homeostasis through checks and balances.

C. elegans are hermaphroditic, meaning they produce both sperm and eggs in the same animal. C. elegans undergoes spermatogenesis in one of its larval stages and when it reaches adulthood, the remaining gametic cells that didn’t become sperm are turned into oocytes so that fertilization can occur.

Small RNA pathways regulate spermatogenesis across species ranging from C. elegans to humans. One class of proteins, Argonautes, are complexed with small RNAs and play an important role in gene silencing. ALG-3 and ALG-4 are two Argonaute proteins in C. elegans that are essential for maintaining thermotolerant male fertility.

“The job of ALG-3 and ALG-4 proteins is to target sperm genes to protect and regulate their expression, to make sure that they’re expressed at the appropriate level during the proper developmental stage,” Rogers said. “Coordinating that spermatogenesis to oogenesis switch at the correct time in development is really important for the fertility of the animal. Defects in the transition between those two biological processes can lead to sterility in the animals.”

RNA is translated into proteins so for every protein, genes need to be expressed and regulated. To get ALG-3 and ALG-4 proteins, the genes encoding them need to be regulated and turned on and off at the appropriate times. If they’re not turned off, ALG-3 and ALG-4 will continue to be produced, leading to continued regulation of sperm genes by ALG-3 and ALG-4.

The team discovered a feedback mechanism where small RNA pathways regulate ALG-3 and ALG-4 expression. They showed that this feedback system is important for providing proper small RNA-mediated control of the sperm genes and spermatogenesis when the animals experience slightly elevated temperatures.

“We discovered that a small RNA mediated regulatory mechanism turns on and off ALG-3 and ALG-4 at the right time of development,” Rogers said. “If you disrupt the small RNA pathways, ALG-3 and ALG-4 were coming on during adulthood, when spermatogenesis should be shut down. That caused a miscoordination or dysregulation of not only ALG-3 and ALG-4 expression, but also regulation of sperm genes by ALG-3 and ALG-4, ultimately leading to sperm-based sterility of the animals during heat stress.”

The discovery of the feedback system for small RNA pathways supports the NIH project, in which the team will try to identify what regulates different aspects of small RNA pathways to maintain homeostasis and proper gene regulation. It also clearly displayed that when the animal is stressed, regulation of small RNA pathways to provide homeostasis is crucial in mitigating the effects of stressors on the animal’s physiological process.

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