If you ever point to your head and say, “The wheels keep turning,” your meaning is clear. And, most likely, you are more right than you know. Within your brain, within individual brain cells, your transcriptional machinery keeps chugging along, turning genes on and off—even switching gears. These gears are the histone spools around which genes are wound. The histone spools in brain cells, it turns out, are constantly being replaced.
This process, called histone turnover, can alter gene expression in response to environmental changes and contribute to neuronal plasticity. It can even account, in part, for the brain’s ability to adapt to changing circumstances.
Histone turnover is a new concept, at least for brain cells, which—unlike many other kinds of cells—do not divide. Nondividing cells were long thought to have highly stable histones. Brain cells, for example, arrive all in one allotment, in the womb, and must last a lifetime. And so it was presumed that brain cells’ epigenetic settings stayed the same.
“We uncover a dramatic developmental profile of nucleosome occupancy across the lifespan of both rodents and humans, with the histone variant H3.3 accumulating to near-saturating levels throughout the neuronal genome by mid-adolescence,” wrote the authors of the Neuron paper. “Despite such accumulation, H3.3-containing nucleosomes remain highly dynamic—in a modification-independent manner—to control neuronal- and glial-specific gene expression patterns throughout life.”
H3.3 is a version of the histone H3 with a small random genetic change in its code, and thus a small difference in its protein structure. Cells with this version of H3 frequently turn over their histones.
To study histone composition in mouse nerve cells and related turnover, researchers fed young, post-weaning rodents a special diet containing lysines that were labeled with heavy isotopes. When examining the nerve cells, researchers explored whether the H3.3 variant was labeled with that stable isotope ("new" histones) or if they were free of the label ("older" histones). This was accomplished by isolating individual neurons from the mice and performing mass spectrometry. The prevalence of the labeled H3.3 demonstrated the fact that the older histones had been replaced with newer ones, indicating histone turnover.
In humans, researchers used a technique called 14C/12C bomb pulse dating to measure turnover. The technique is based on the fact that high levels of radioactive carbon (14C) were released into the atmosphere during the 1950s and 1960s, when open-air nuclear bomb testing occurred following the Second World War. Researchers can take samples from cells (in this case, purified H3.3 samples from brain cells of postmortem human brains) and determine present 14C/12C ratios from the time of death against past atmospheric levels from the time of the subject's birth. As with the rodent observations, the researchers found that H3.3 turnover occurs in the human brain throughout life.
Additionally, the researchers deliberately manipulated H3.3 dynamics in both embryonic and adult neurons, confirming the role of histone turnover in neuronal plasticity. The findings thus establish histone turnover as a critical, and new, regulator of cell-type specific transcription in the brain.
"Histone turnover, shown through our work with H3.3, is essential for the behavior of brain cells," said Dr. Maze, lead study of the Neuron paper and an assistant professor of pharmacology and systems therapeutics at the Icahn School of Medicine. "Furthering our understanding of how the brain works, learns, forms new memories, and reacts to changes in the environment can help us to find new ways to treat neurodegenerative diseases and mental illness."