Amazing stuff! Good news!
"... "We have uncovered a new biological process linking experience of early-life adversity to this long-term vulnerability to mental illness," ...
"This finding reveals a physical scar left by trauma experienced during development inside brain cells, providing scientists with a concrete biological target to develop new treatments and interventions." ...
The researchers found that an enzyme called SETD7 was more abundant in the dopamine neurons of young mice that had experienced stress compared with mice reared in a typical environment.
SETD7 helps place a chemical tag—H3K4me1—on the genetic slinky [coiled DNA]], marking the structure for uncoiling, which in turn makes the cell more reactive to everything going on in the environment, Peña explained.
The researchers then artificially boosted SETD7 in young, stress-free mice. Even without early-life stress, these mice grew up with a stretched-open DNA structure in their dopamine-producing brain cells, making it easier to turn on the genes that respond to stress. Such mice had a lower tolerance for stress in adulthood.
The researchers found that, as adults, mice whose SETD7 levels had been boosted when they were young had more reactive dopamine neurons and more anxious behavior compared with mice with normal levels of SETD7 throughout their lives.
Conversely, when the researchers blocked the SETD7 enzyme from adding too much of the H3K4me1 tag after early-life stress, the slinky remained closed, shielding mice from becoming hypersensitive to stress later in life. Despite experiencing both early-life and adult stress, mice with their SETD7 levels dampened were able to remain as social and exploratory as unstressed mice, and their dopamine neurons were active at normal levels. ..."
From the highlights and abstract:
"Highlights
• Early-life stress increases H3K4me1 and the monomethyltransferase SETD7 in VTA
• Setd7-OE heightens gene expression, dopaminergic, and behavioral responses to stress
• Setd7 knockdown in VTA ameliorates the impact of early-life stress
• Such epigenetic priming is a novel mechanism for encoding lasting stress sensitivity
Summary
Early-life stress increases gene expression, neurophysiological, and behavioral responses to subsequent stress.
Here, we determined the role of chromatin in such long-lasting sensitivity. We used a combination of bottom-up mass spectrometry, viral-mediated epigenome editing, RNA sequencing, patch-clamp electrophysiology of dopamine neurons, and behavioral quantification in a mouse model of early-life stress, focusing on the ventral tegmental area (VTA), a key dopaminergic brain region.
We found that early-life stress enriches histone-3 lysine-4 monomethylation—associated with open chromatin and primed or active enhancers—and the H3K4 monomethylase SETD7.
Mimicking early-life stress through postnatal overexpression of Setd7 and enrichment of H3K4me1 in the VTA sensitizes transcriptional, physiological, and behavioral responses to adult stress, while Setd7 knockdown ameliorates the impact of early-life stress.
These findings link early-life stress experience to long-term stress hypersensitivity within the brain’s dopaminergic circuitry, providing a mechanism by which early-life stress increases risk for mood and anxiety disorders later in life."
Graphical abstract:
Figure 3 Juvenile Setd7 overexpression augments transcriptional responses to adult stress
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