A new discovery for how DNA unwinds in neurons to support brain health and memory
Emily Feierman was the lead author on this study. Emily is currently a postdoc in the labs of Kiran Musunuru and Becca Ahrens-Nicklas at Penn/CHOP developing gene editing therapies for rare pediatric metabolic disorders.
or technically,
Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory
[See Original Abstract on Pubmed]
Authors of the study: Emily R Feierman, Sean Louzon, Nicholas A Prescott, Tracy Biaco, Qingzeng Gao, Qi Qiu, Kyuhyun Choi, Katherine C Palozola, Anna J Voss, Shreya D Mehta, Camille N Quaye, Katherine T Lynch, Marc V Fucillo, Hao Wu, Yael David, Erica Korb
While most of us know about the famous double-stranded structure of DNA, what is much less common knowledge is how DNA is stored inside of our cells. Think about it… a single cell in your body has so much DNA that if you laid it out, it would be almost 2 meters (or 6 and a half feet) long! In a flash back to biology class, you may remember that DNA is stored in 23 pairs of chromosomes in each cell which look like big fuzzy ‘X’s. And as it turns out, each of those chromosomes is really made up of DNA wrapped around lots of big blocky proteins called histones, almost like string wound around a bunch of yo-yos and stacked next to each other.
When a cell wants to read a gene from the DNA to make a new protein, it uses different mechanisms to partially unwind those histone yo-yos.This type of control (opening and closing access to DNA without changing the DNA itself) is called epigenetics. It helps cells decide which genes to use and when. This is especially important in the brain, where neurons need to turn on certain genes for learning, communication, and memory. Epigenetics is a very hot field of research because when this regulation goes wrong, cells may activate the wrong genes or fail to activate the right ones, which can contribute to neurological disease.
Emily Feierman, a recent NGG graduate, and her lab wanted to know how epigenetics plays a role in the brain – specifically how different histones can modify how tightly packed the DNA is in neurons across the brain and whether or not this can affect thinking and memory. To do this, she looked at a newly discovered component of the ‘yo-yos’, a histone protein called H2BE.
Before we talk more about H2BE we have to know a bit more about histones. Each ‘yo-yo’ is made up of four different histones which are usually standard. These are called H2A, H2B, H3, and H4. But it turns out, your cells can actually substitute in some less common histones to loosen up the DNA and allow different genes to be expressed. Each of the 4 standard histones can come in those less common flavors. While previous studies had found these flavor variants in the brain for H2A and H3, nobody had yet found any widely present flavors of the standard H2B histone building block.
Emily and her team were interested in ‘E’ variant of H2B specifically because over a decade ago H2BE had been shown to be highly present in neurons of the olfactory cortex of the brain, the area responsible for your ability to smell, but it wasn’t clear at the time whether or not it was present in the rest of the brain or what exactly it was doing.
To remedy this, Emily developed a new way to mark the presence of H2BE in neurons and found that instead of existing only in the olfactory area, it can actually be found in neurons all across the cortex of the brain. This suggests that it plays an important and more general role in supporting neurons since it’s found everywhere across the brain instead of just one area. She also found that H2BE loosens up the DNA strands more than normal H2B, so that genes can be more easily read out for protein production. But what proteins does H2BE help free up for production you may ask?
To answer this question, Emily used a mouse model gene knockout (KO) of H2BE, meaning the mice could not produce H2BE, and harvested neurons from their brains and compared the range of genes turned on in these mice relative to normal mice. She found that neurons from H2BE KO mice had changes in genes related to the functioning of neuronal synapses, the sites of contact between neurons that allow them to communicate.
One thing to know about synapses is that they are complicated button-like structures on the branches of neurons that require a lot of maintenance. Like little machines, they require scaffolding to build and molecular gizmos to make work, which requires a lot of different proteins to be made and therefore genes to be active. So any changes in synaptic gene expression in the H2BE KO mice might lead to impaired synaptic functions. When Emily tested this, this is exactly what she found - neurons from H2BE KO mice had reduced synaptic responses to electrical inputs.
It is also well known that the ‘strength’ of synapses and their density in neurons can play a role in memory formation. To test if H2BE plays a role in memory, Emily subjected the H2BE KO mice that have the deficits in synaptic functioning to different behavioral and memory tasks. While they didn’t seem to have any problems with their sense of smell, social activity, or anxiety, they did have reduced long term memory!
So it seems that by epigenetically controlling the looseness of DNA at key sites related to proteins used for synaptic functioning, the histone H2BE variant plays an important role in maintaining neuronal health and memory formation. Emily’s work is the first to fully characterize the role of this histone variant in brain functioning, and it opens up new insights into how gene expression is controlled in neurons to ultimately contribute to behavior, and how it could go wrong in aging and disease.
About the brief writer: Joe Stucynski
Joe is a graduate student in Dr. Franz Weber’s and Dr. Shinjae Chung’s labs at Penn. He is interested in how the immune system influences sleep regulation during sickness via interoceptive pathways.