“Half of what you learned in college is wrong,” my biology professor, David Lange, once said. “Problem is, we don’t know which half.” How right he was. I was taught to scoff at Jean-Baptiste Lamarck and his theory that traits acquired through life experience could be passed on to the next generation. The silly traditional example is the mama giraffe stretching her neck to reach food high in trees, resulting in baby giraffes with extra-long necks. Then biologists discovered we really can inherit traits our parents acquired in life, without any change to the DNA sequence of our genes. It’s all thanks to a process called epigenetics — a form of gene expression that can be inherited but isn’t actually part of the genetic code. This is where it turns out that brain chemicals like dopamine play a role.
Inherited genes are activated or inactivated to build a unique individual from a fertilized egg, but cells also constantly turn specific genes on and off throughout life to make the proteins cells need to function. When a gene is activated, special proteins latch onto DNA, read the sequence of letters there and make a disposable copy of that sequence in the form of messenger RNA. The messenger RNA then shuttles the genetic instructions to the cell’s ribosomes, which decipher the code and make the protein specified by the gene.
But none of that works without access to the DNA. By analogy, if the magnetic tape remains tightly wound, you can’t read the information on the cassette. Epigenetics works by unspooling the tape, or not, to control which genetic instructions are carried out. In epigenetic inheritance, the DNA code is not altered, but access to it is.
This is why cells in our body can be so different even though every cell has identical DNA. If the DNA is not unwound from its various spools — proteins called histones — the cell’s machinery can’t read the hidden code. So the genes that would make red blood corpuscles, for example, are shut off in cells that become neurons.
How do cells know which genes to read? The histone spool that a specific gene’s DNA winds around is marked with a specific chemical tag, like a molecular Post-it note. That marker directs other proteins to “roll the tape” and unwind the relevant DNA from that histone (or not to roll it, depending on the tag).
It’s a fascinating process we’re still learning more about, but we never expected that a seemingly unrelated brain chemical might also play a role. Neurotransmitters are specialized molecules that transmit signals between neurons. This chemical signaling between neurons is what enables us to think, learn, experience different moods and, when neurotransmitter signaling goes awry, suffer cognitive difficulties or mental illness.
Serotonin and dopamine are famous examples. Both are monoamines, a class of neurotransmitters involved in psychological illnesses such as depression, anxiety disorders and addiction. Serotonin helps regulate mood, and drugs known as selective serotonin reuptake inhibitors are widely prescribed and effective for treating chronic depression. We think they work by increasing the level of serotonin in the brain, which boosts communication between neurons in the neural circuits controlling mood, motivation, anxiety and reward. That makes sense, sure, but it is curious that it usually takes a month or more before the drug relieves depression.
Dopamine, on the other hand, is the neurotransmitter at work in the brain’s reward circuits; it produces that “gimme-a-high-five!” spurt of euphoria that erupts when we hit a bingo. Nearly all addictive drugs, like cocaine and alcohol, increase dopamine levels, and the chemically induced dopamine reward leads to further drug cravings. A weakened reward circuitry could be a cause of depression, which would help explain why people with depression may self-medicate by taking illicit drugs that boost dopamine.
But (as I found out after reading that dopaminylation paper), research last year led by Ian Maze, a neuroscientist at the Icahn School of Medicine at Mount Sinai, showed that serotonin has another function: It can act as one of those molecular Post-it notes. Specifically, it can bind to a type of histone known as H3, which controls the genes responsible for transforming human stem cells (the forerunner of all kinds of cells) into serotonin neurons. When serotonin binds to the histone, the DNA unwinds, turning on the genes that dictate the development of a stem cell into a serotonin neuron, while turning off other genes by keeping their DNA tightly wound. (So stem cells that never see serotonin turn into other types of cells, since the genetic program to transform them into neurons is not activated.)
That finding inspired Maze’s team to wonder if dopamine might act in a similar way, regulating the genes involved in drug addiction and withdrawal. In the April Science paper that so surprised me, they showed that the same enzyme that attaches serotonin to H3 can also catalyze the attachment of dopamine to H3 — a process, I learned, called dopaminylation.
Together, these results represent a huge change in our understanding of these chemicals. By binding to the H3 histone, serotonin and dopamine can regulate transcription of DNA into RNA and, as a consequence, the synthesis of specific proteins from them. That turns these well-known characters in neuroscience into double agents, acting obviously as neurotransmitters, but also as clandestine masters of epigenetics. (...)
To put it plainly, the discovery that monoamine neurotransmitters control epigenetic regulation of genes is transformative for basic science and medicine. These experiments show that the tagging of H3 by dopamine does indeed underlie drug-seeking behavior, by regulating the neural circuits operating in addiction.
And, equally exciting, the implications likely go well beyond addiction, given the crucial role of dopamine and serotonin signaling in other neurological and psychological illnesses. Indeed, Maze told me that his team’s latest research (not yet published) has also found this type of epigenetic marking in the brain tissues of people with major depressive disorder. Perhaps this connection even explains why antidepressant drugs take so long to be effective: If the drugs work by activating this epigenetic process, rather than just supplying the brain’s missing serotonin, it can take days or even weeks before these genetic changes become apparent.
