miRNAs: Fine-tuning gene expression
Little bits of RNA that are very important to your health.
Hi everyone -
I'm going in a slightly different direction this week and bringing you a science explainer article with a few genes thrown in as examples.
I'll be including more in Genetic Lifehacks articles on how your body controls gene expression on top of your DNA -- touching on epigenetics and post-translational modifications (like miRNA) in many topics.
People in holistic health and nutrition often say things that aren't quite accurate about epigenetics and gene expression. "I have that gene, but it isn't expressing because I cleaned it up so it's turned off".
While I understand what they're getting at, I've decided it's time to include a basic framework around gene expression and write more about it on Genetic Lifehacks. I'm not an expert here, so I'm learning along with all of you as I research and write the article.
I'm starting with microRNAs (miRNA).
One reason to start here is that miRNAs are coded for in your DNA -- and there are some interesting SNPs in your raw data files that I'm going to go back and add to prior articles. Yes, I was lazy and had left them out because I didn't want to explain miRNA.
Another reason is that I suspect that the effect of environmental toxins on gene expression, including by altering miRNA levels, is the key to many of the health problems we face today.
The last reason to cover miRNA is that there is a ton of new research on it for drug development. I want all of you to have a head start on understanding what these short strands of RNA are doing in your cells before the miRNA drugs hit the market.
The first half of the new article is included below, along with a link for members to click through to the website to read the rest and see a few examples of their miRNA genes.
Stay curious with me :-)
~ Debbie
miRNA: What It Is and How It Works
Key takeaways:
~ miRNAs are small non-coding RNA molecules that regulate gene expression.
~ miRNAs are important in many different biological processes, including cancer growth, immune response, cardiovascular disease, and longevity.
~ Exposure to environmental factors, such as PFAS, heavy metals, and BPA, can alter miRNA levels, which then affects the expression of other genes.
MicroRNA: Controlling Gene Expression
On Genetic Lifehacks, I write about how your genes make you unique and a little different from everyone else. Variants in protein-coding genes make us all individuals, requiring slightly different nutrients, responding differently to pathogens, and predisposing us to different chronic diseases.
The central dogma of biology is that genes are transcribed into mRNA in the cell nucleus. This mRNA then travels to the cytosol of the cell where it is translated by ribosomes into the corresponding protein.
Gene –> mRNA –> Protein
We have around 20,000 protein-coding genes in the human genome, but that’s only a small portion of our DNA.[ref]
Our DNA also encodes RNAs that aren’t translated into proteins. These are called non-coding RNA genes. There are currently more than 7,000 known and named RNA genes. They are divided up and classified by size and function — microRNAs, transfer RNAs, long non-coding RNAs, circular RNAs, small interfering RNAs, small nuclear RNAs, and ribosomal RNAs.[ref]
MicroRNA, or miRNA, is a small strand of RNA that controls gene expression. Gene expression here refers to how much of the corresponding protein is made from a gene. Specifically, miRNAs regulate gene expression post-transcriptionally.
How microRNAs control gene expression:
Specific miRNAs can bind to specific sequences in mRNA and prevent the mRNA from being translated into the protein. This can either cause the mRNA to be degraded and recycled, or it can just cause a temporary delay in the translation into the protein.
Let me give you an example:
MicroRNA-21 (miR-21) is a well-studied microRNA that controls gene expression for many genes involved in growth, including PTEN and RHOB, which are important in cancer growth. Hypoxia, or a lack of oxygen, in the tumor tissue, increases miR-21, which then helps the cells proliferate and grow.[ref]
This isn’t just a rare occurrence: About 60% of genes get translated into mRNA that can be then bound by a miRNA and silenced.[ref]
In addition, a specific miRNA can control the expression of multiple genes, with some controlling the expression of hundreds of different genes.[ref][ref]
The amount of miRNA matters in regulating gene expression. If you have more than the normal amount of a specific miRNA, then you will have less than the normal amount of certain proteins produced. Likewise, if you have less than the normal amount of an miRNA then you’ll have more of the protein that it controls.
SNPs – single nucleotide polymorphisms – can change the way that a protein-coding gene works. As an example, MTHFR C677T is a well-known SNP that alters the way that folate is used for the methylation cycle.
Similarly, SNPs in miRNAs can alter the function and level of an miRNA. This can then affect the expression of hundreds of other genes. To make things even more complex, SNPs in protein-coding genes that affect the miRNA binding site can then change the way gene expression is controlled for that gene[ref][ref] (I’ll include a few miRNA SNPs below in the genotype report as examples.)
One cool thing about miRNAs is that they can be packaged into vesicles and shed from the cell. This allows them to circulate and be taken up by other cells.[ref]
Quick history lesson:
MicroRNAs were discovered in the early 1990s. Researchers at Harvard and Massachusetts General discovered lin-4, which regulated the timing of development in C. elegans through post-translational regulation. Since then, miRNAs have been found to regulate protein expression in plants, animals, and all multicellular organisms. The 2024 Nobel Prize in Physiology or Medicine was awarded to Victor Ambros (Harvard, UMass) and Gary Ruvkun (Mass General, Harvard) for the discovery of microRNA and its role in post-transcriptional gene regulation. Their breakthrough challenged and refined ideas about post-translational gene expression.[ref]
Why are miRNAs important in health and longevity?
MicroRNAs control the expression of many different proteins, so higher or lower levels of miRNAs directly affect many cellular functions. They are sometimes referred to as “fine tuners” of gene expression because they can turn up or down the amount of a protein in response to changing environmental conditions – such as stress or injury..[ref]
Aging: Studies on aging and longevity show that miRNAs are an integral part of the aging process. Many miRNAs are expressed at higher or lower levels during aging and can have either positive or negative effects on longevity. Modulating miRNA expression is one way to increase lifespan in animal models[ref]
A new study (Jan 2025) in mice used an oral miRNA compound to reverse aging. The researchers gave old mice exosomes containing miR-302b, which reversed cellular senescence. This is a cool study with nice pictures of old mice looking young, but cellular senescence is also one of the brakes that stops cancer. More research is definitely needed here.[ref]
Cancer: About half of the known miRNA genes are involved in regulating the expression of genes related to cell division, growth, proliferation, or apoptosis. Uncontrolled cell growth or lack of restriction of cell growth can lead to cancer. Therefore, miRNAs are a hot topic in cancer research.[ref]
Immune response: MicroRNAs play an integral role in our immune response to viral and bacterial pathogens. For example, miR-155 affects interferon response, natural killer cell activity, and T-cell response to viral infections.[ref] The immune response to mold is also regulated by miRNAs, including miR-155, miR-21, and miR-146.[ref]
miRNAs can compete with each other in modulating the immune response. For example, miR-146 can repress NF-κB activation, but miR-155 overexpression can override miR-146. This is a kind of feedback mechanism that the body can use at different times to dial in the immune response.[ref]
Cardiovascular disease: Much research has been done on the effects of various miRNAs in cardiovascular disease. For example, researchers found that miR-29 likely regulates collagen and other matrix proteins that are involved in cardiac fibrosis. A miR-29 mimic has been developed and used in mice to reverse cardiac fibrosis.[ref]
Neurodegenerative diseases: MicroRNAs affect both the physical structure of the brain through nerve growth and the function of the brain through regulating neurotransmitter levels.[ref]
A 2008 study found that miRNA-146a was upregulated in Alzheimer’s brains. This corresponded to a downregulation of complement factor H, which is part of the innate immune system. Complement factor H binds to APOE2 and APOE3, but not to APOE4, which is thought to be part of the reason why APOE4 increases the risk of Alzheimer’s.[ref] [ref] TREM2 genetic mutations are a risk factor for earlier Alzheimer’s disease. Overexpression of miR-34a inhibits TREM2 expression in the brain, which interferes with the clearance of amyloid-beta plaques.[ref]
Future of miRNAs:
There is a lot of recent research into miRNAs because they can be easily synthesized and packaged into exosomes as an oral drug, which means there is a lot of money available for the research.
The problem with miRNAs is that there is a wide range of effects, many of which can be off-target. A phase I clinical trial involving a miR-34 mimic (MRX34) for advanced solid tumors showed efficacy with 3 patients having a positive response, but there were also serious immune-mediated adverse events that caused the death of 4 patients.[ref]
What I've been reading:
1.) Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration
Intermittent fasting inhibits the regeneration of hair follicles in mice and in humans due to the release of cortisol from the adrenals. Fasting triggers cues to the body that there isn't enough food, so the body smartly shuts down processes that aren't a priority, like hair growth.
There's a big push for GLP-1 RA drugs these days, but there are some serious side effects to take into consideration.
From the study: "the study included 162,253 case and control patients. This study showed a significant association between GLP-1 RA treatment and an 98% increased risk of any psychiatric disorders. Notably, patients on GLP-1 RAs exhibited a 195% higher risk of major depression, a 108% increased risk for anxiety, and a 106% elevated risk for suicidal behavior."