A post-translational modification of histones linked to permanent susceptibility to stress in mice

Chemical modifications of histones, proteins that help package and organize DNA inside cells, play a key role in determining which genes will be constantly activated over the life of an animal or animal. a human. Previous studies have highlighted certain chemical alterations of histones that occur after these proteins are translated in a cell, which may increase people’s susceptibility to specific disorders or diseases.

Researchers at the Icahn School of Medicine at Mount Sinai recently identified a particular post-translational modification of histones linked to greater susceptibility to different types of stress in mice. This modification, described in an article published in Neuronis the mono-methylation (the addition of a methyl group) of the 27th amino acid lysine in the histone H3 protein, also called H3K27me1.

“We have known for decades that adverse experiences ‘scar’ our brains and influence how we respond to various stressors,” Dr. Angelica Torres-Berrio, co-author of the paper, told Medical Xpress. “These ‘scars,’ which serve as an analogy for epigenetic factors, can persist for a lifetime and facilitate or prevent the expression of a specific set of genes.

“In this study, we sought to determine whether post-translational modifications of histones, essential proteins that dictate DNA availability and readiness of genes for expression, can serve as ‘epigenetic scars’ that mediate the impacts negative effects of stress.”

Dr. Torres-Berrio, Dr. Eric J. Nestler, and their colleagues specifically focused their analyzes on mice with nucleus accumbens (NAc). It is a region of the mammalian brain known to contribute to mood regulation, motivation, and cognitive control.

Previous studies have shown that certain post-translational modifications of histones in this region may increase the risk of developing certain psychiatric disorders, including depression and anxiety. Torres-Berrio, Nestler and their colleagues sought to determine which of the hundreds of changes identified in the past specifically caused greater susceptibility to stress.

“We combined a variety of techniques from molecular analyzes to complex behavioral tasks,” Torres-Berrio explained. “First, we profiled hundreds of histone modifications from the NAc of mice exposed to chronic social defeat stress (ELS) or mice previously exposed to early life stress (ELS), using mass spectrometry. Through this unbiased proteomic approach, we identified H3K27me1 as the lead candidate for stress susceptibility in these two mouse models. These changes were selectively observed in D1 neurons of the NAc.

After profiling hundreds of histone modifications in the NAc of mice exposed to stress, the researchers used a technique known as CUT & RUN (cleavage under targets and release using nuclease) to discover genes or DNA segments that interacted with the H3K27me1 modification. This revealed that this particular modification binds to genes involved in the functioning of ion channels and synaptic receptors.

“We then explored the mechanism that might regulate H3K27me1 enrichment and focused on polycomb repressive complex-2 (PRC2), a protein complex that regulates methylation of lysine 27 (K27) on histone 3.” , Torres-Berrio said. “Thus, we measured EZH2, SUZ12, and EED protein and RNA expression in CSDS-susceptible mice. Of these, only SUZ12 was significantly different.”

Torres-Berrio, Nestler, and colleagues next attempted to confirm whether the SUZ12 protein helped regulate H3K27me1 modification and thus played a role in conferring greater susceptibility to stress in mice. To do this, they expressed the functional domain (VEFS domain) of this protein in D1 neurons of the NAc, a class of brain cells that play a key role in pleasure- and reward-seeking behaviors.

“This experimental manipulation was sufficient not only to increase H3K27me1 abundance, but also to alter the transcriptional and physiological signatures of the NAc,” Torres-Berrio said. “Remarkably, this manipulation made the mice more vulnerable to the effects of stress. They demonstrated social avoidance and low motivation to interact with other mice or were unable to switch between learning strategies. to another, which is a sign of inflexible behavior.”

This recent study is the first to establish the crucial function of H3K27me1 in the mouse brain, particularly in the regulation of vulnerability to stress. Additionally, researchers revealed specific genes in Nac whose transcriptional potential is affected by aberrant enrichment of this histone modification.

“While post-translational modifications of histones are recognized as important mediators of the prolonged effects of stress, researchers in the field have long focused on the repressive mark H3K27me3 or the enhancer-associated mark H3K27ac, leaving other modifications of totally understudied histones,” Torres-Berrio said. .

“Through our unbiased histone profiling approach, we discovered that H3K27me1 was a common alteration in distinct mouse stress models. This finding is critical to our understanding of the complex neurobiology of stress, as there is evidence that Different stress patterns can induce variations, even opposite, molecular changes in the brain, making it difficult to determine a single mechanism.”

The recent work of Torres-Berrio, Nestler and their colleagues constitutes a significant contribution to the study of stress and its underlying neurobiological processes. The post-translational modification of histones identified by the team may soon be the subject of further studies examining both animals and humans.

“Prior to our study, almost nothing was known about how H3K27me1 functions in the brain, either during development or in response to harsh environments,” Torres-Berrio added. “Thus, the next step is to explore how H3K27me1 and its regulatory mechanism can contribute to the development of better treatments for depression and stress-related disorders.”

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