Could epigenetics be a risk factor for suicide?

Epigenetic mechanisms drive changes in brain protein concentrations, which in turn may contribute to suicidal behaviours, according to a recent study.

“Our findings confirm the role of epigenetic component and brain-derived neurotrophic factor (BDNF) protein in suicidal behaviour,” researchers said. “Lowered BDNF protein level in suicides is probably due to decrease in histone acetylation and increased level of factors related with deacetylation and methylation processes.”

Western blot analysis on brain tissues showed that acetylation on the ninth and 14th lysine residues of histone H3 (H3K9/14ac) was reduced by 33.1 percent in the hippocampus of suicide victims than in controls. The Mann-Whitney U-test revealed a statistically significant difference (p=0.0441). [PLoS One 2020;15:e0239335]

The same epigenetic marker was likewise suppressed by a significant 22.8 percent in the frontal cortex of victims vs controls (p=0.009).

This drop in histone H3 acetylation corresponded with a spike in the concentrations of the histone deacetylase 3 (HDAC3) protein in the brains of victims. In the hippocampus and frontal cortex, HDAC3 levels were enriched by 85.3 percent (p=0.010) and 102.8 percent (p=0.014), respectively. A slight and nonsignificant increase in HDAC2 was also detected in suicide victims.

Spearman’s rank correlation analysis showed a significant interaction between HDAC3 and H3K9/14ac in the hippocampal region of the brains of suicide victims (r, –0.560; p=0.037), but no such effect was found in the frontal cortex.

The researchers also observed statistical increases in the demethylation of the 27th lysine residue of histone H3 (H3K27me2) in the hippocampus (58.9 percent; p=0.0221) and frontal cortex (45.0 percent; p=0.018) of suicide victims as compared to controls. A similar effect was reported for SIN3 transcription regulator family member A (sin3a; hippocampus: 50.0 percent; p=0.028).

At the same time, there were significant disparities in BDNF protein levels, which were reduced by 28 percent (p=0.005) in the hippocampus and by 42.03 percent (p=0.019) in the frontal cortex, of the suicide victims.

“Suicide is a common phenomenon affecting people of all ages. There is a strong relationship between suicidal ideation and depressive disorders,” the researchers said.

They pointed out that in recent years, more and more studies have suggested that “epigenetic modifications in certain brain areas are the main mechanism through which environmental and genetic factors interact with each other contributing to the development of mental disorders.”

The present study sought to verify this hypothesis by conducting a postmortem analysis on brain tissues of 14 victims of suicide and eight who had died from unexpected sudden deaths. None of the victims were diagnosed psychiatrically, and none of the participants could be identified.

“[O]ur study for the first time describes alterations in the BDNF levels in suicide victims on the background of serious and multidimensional epigenetic changes both in the frontal cortex and hippocampus,” the researchers said. “The obtained results contribute to a better understanding of the mechanisms underlying the suicidal behaviour.”

“The mechanisms of epigenetic regulation of gene expression in the brain seems to be very complicated, multidirectional, and structure-dependent; therefore, further, extended studies should be undertaken to find reliable epigenetic markers associated with suicide,” they added.