Entries in epigenetics (3)

Thursday
Apr212016

Epigenetics and our sense of smell

The olfactory sensory neurons (OSNs) are a unique population of neurons that allow us to detect and identify specific odorants. The odorants are detected when they bind to specific olfactory receptors (ORs) expressed by the OSNs. Once an odorant is bound, a signaling cascade is initiated to notify neurons in the adjacent olfactory bulb and the rest of the olfactory pathway that the odorant is present.  

Usually, OSNs express a single olfactory receptor, and the axons of all OSNs that express the same OR meet at the same location within the olfactory bulb. It’s a great system – all inputs for a particular odor meet up in the same region of the olfactory bulb, presumably to consolidate and simplify the odor signals received by the brain.

But this system is also complex. It relies on each and every OSN expressing a single OR. In mice, this requires a selection of one OR out of a possible 1,400. Once chosen, the OR selection needs to be maintained throughout the life of the neuron, or bananas might start to smell like garbage.

On the surface, it makes sense that epigenetic regulation would be involved in the OR selection process – as one gene must be expressed in the face of a multitude of options. But how does this actually happen?

A recent study by Lyons, DB et al (1), used an army of mouse models to parse out important protein expression patterns necessary for the installment of a single OR in a single OSN. To begin, they found that the epigenetic protein lysine-specific demethylase 1 (LSD1) is involved in de-silencing individual ORs through histone H3 lysine K9 (H3K9) demethylase activity.  This initial process allows the next step to occur, transcriptional activation through histone H3 lysine K4 (H3K4) trimethylation, which initiates production of the OR.

So how is the selective expression of a single OR maintained? This is achieved through induction of adenylate cyclase 3 expression by the OR. Adenylate cyclase 3 expression downregulates LSD1 expression, and prevents the transcriptional activation of other ORs. Thus, once Adenylate cyclase 3 is expressed, the neuron becomes “trapped” through a feedback loop into making a single OR. And there you have it – bananas continue to smell like bananas.

 ~GV

1)     Lyons DB, Allen WE, Goh T, Tsai L, Barnea G, Lomvardas S. An epigenetic trap stabilizes singular olfactory receptor expression. Cell, 2013, 154, 325-336.

Tuesday
Jan122016

Epigenetics rules the ant kingdom

Typically in an ant colony, roles are split among workers based on their physical characteristics.  There are two major paths for workers of a colony.  One type, which consists of about one-third of the workers, are called majors.  The other workers are smaller and are called minors.  Minors typically forage for food much more often compared to the majors, who are much larger in comparison to their counterpart. 

What researchers have discovered about the caste system in a colony of carpenter ants is that both the size and the occupation that the worker ants acquire are based on epigenetic characteristics in their DNA.  Researchers at University of Pennsylvania conducted a study in which they administered two mood-stabilizing drugs to specific subjects within the colony through brain injection. After, they observed their overall foraging and scouting behavior.  Overall, they found that after an increase in histone acetylation (through the use of the bipolar drug) in the ants, minors foraged more aggressively and starting scouting for new food.  Majors began to exhibit foraging behavior, which is a characteristic usually only seen in minors. The effects of the drug treatment lasted for up to 50 days. They also found that the overall ability to change the behavior was greater in younger workers, suggesting a timeframe in which ants are more susceptible to being influenced by drug treatment at a younger age. 

More importantly, this research suggests a possible mechanism to the nurture component in the nature versus nurture dispute.  It also highlights the importance of epigenetic markers and the need for more research in epigenetics. In addition, researchers think that certain social situations could influence epigenetic changes in vertebrate species, giving clues to biologic mechanisms involved in social interactions and behaviors.

"Epigenetic (re)programming of Caste-specific Behavior in the Ant Camponotus Floridanus." Science 351.6268. 2015.

Tuesday
Jun022015

Exciting promise for epigenetic-based pain therapeutics

As a consequence of growing up in Buffalo, NY, I have never adjusted well to high temperatures. This became a bit of a problem in graduate school, when I lived in Baltimore, MD (summer average temperature is around 90F!). One morning I was particularly motivated and went for a jog, it was only 80 degrees; I thought I would be fine!  However, when I was only two miles into my routine (no problem at that time…) I broke out in a cold sweat, became dizzy, and felt instantly nauseous and weak. It was AWFUL! Luckily, I recognized these symptoms and rested in the shade until I could safely walk home. But what if these symptoms didn’t occur? What if I hadn’t felt awful? Likely, I would have suffered a serious heat stroke. Such what-if’s are a constant concern for people with CIP (congenital insensitivity to pain). Without pain, everyday activities become dangerous.

CIP is a rare autosomal recessive genetic disease that results in a complete loss of pain perception1. Patients cannot feel extreme injuries such as a broken bone or a third-degree burn2,3,4. Consequently, continual self-mutilation results in lesions to the tongue, bone deformities, corneal scarring, and neuropathic joints5. Patients also cannot recognize signs of internal illness such as infection4. Therefore, those with CIP must diligently survey themselves to access their health daily.

Recently, Chen et al. discovered a set of CIP-related mutations in the PRDM12 gene5. PRDM12 encodes a SET domain protein expressed in nociceptors (pain-sensing neurons) and is required for nociceptor development5. Unlike most SET domain proteins, PRDM12 does not have intrinsic histone methyltransferase activity; instead PRDM12 recruits G9a to dimethylate histone H3 at the lysine 9 position (H3K9me2)5. CIP-related mutations disrupt G9a recruitment and therefore, the histone-modifying potential of PRDM125. Accordingly, precise localization of H3K9me2 during nociceptor development may be essential for pain sensation.

Although too little pain is dangerous, chronic pain is a huge problem for over 100 million Americans6. Inhibition of PRDM12 may provide a promising target for pain therapeutics. It will be interesting to learn the in vivo effects of PRDM12 inhibition in rodent pain models. As current opioid-based pain medications are highly addictive, new pain management treatments represent a huge medical need.

~TG

1.)  Peddareddygari, Oberoi, and Grewal (2014). Congenital Insensitivity to Pain: A Case Report and Review of the Literature. Case Reports in Neurological Medicine.

2.)  Genetics Home Reference (2012). Congenital Insensitivity to Pain. Retrieved from http://ghr.nlm.nih.gov/condition/congenital-insensitivity-to-pain

3.)  ABC News (2013). Meet the Child Who Feels No Pain. Retrieved from http://abcnews.go.com/Health/meet-toddler-feels-pain/story?id=20658484&page=2

4.)  Chen et al. (2015). Transcriptional regulator PRDM12 is essential for human pain perception. Nature Genetics Letters.