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Epigenetics: nature meets nurture in psychiatry.

Epigenetics is a biological process whereby the environment and experience influence and regulate the expression of the human genome. This discovery resolves the centuries-old nature/nurture debate about the primary effectors of our biological constitution and our ability to modify our inheritance. This is clearly relevant to how we address psychiatric disorders and brain plasticity, a biologically adaptive process that involves gene regulation via epigenetic factors. Our understanding of epigenetic biological mechanisms within the brain offers a promising new paradigm related to the pathophysiology of psychiatric disorders and the potential to address them at their root cause. Pharmacological and nonpharmacological treatments that target gene expression afford a novel opportunity to treat brain disorders that were once regarded as intractable.

The physical barrier to gene transcription occurs by restricting access to the underlying genomic DNA. Epigenetic regulation involves access to regulatory regions comprising histone-modifying enzymes at specific CpG sites. CpG sites are regions of DNA wherein a cytosine nucleotide becomes methylated through DNA methyltransferase enzymes which have the net effect of suppressing gene transcription. The attachment of a methyl group to cytosine is catalyzed by a family of enzymes known as DNA methyltransferases. About 60% to 75% of mammalian gene promoters reside within CpG islands, suggesting that these regions are the key regulatory sites of gene expression. (1)

The manipulation of these CpG islands through methylation or demethylation is instrumental in regulating gene expression for a number of processes in the brain, particularly the maintenance and consolidation of long-term memory. (2) Epigenetic control of DNA expression strengthens specific synaptic connections over others and is the specific mechanism whereby experience and environment can exert physical changes within the brain. In addition to methylation, epigenetic mechanisms that regulate gene transcription may also involve acetylation via histone acetyltransferases and histone deacetylases (HDACs), all of which act in a concerted fashion to determine the activity of a given gene. Histone acetyltransferases add acetyl groups causing the chromatin surrounding DNA to be in a relaxed state to promote gene expression. Conversely, histone deacetylases work by promoting transcriptional repression. There is substantial crosstalk between DNA methylation and histone modifications which involves interaction between DNA methyltransferase enzymes and histone-modifying enzymes. (3) As mentioned above, DNA can be methylated via DNA methyltransferases (DNMTs), which occur at CpG sites that repress gene activity. The carefully coordinated balance of methylation/demethylation as well as histone acetylation/ deacetylation is what ultimately determines gene expression resulting from epigenetic environmental influences. It is precisely this balance that is required for synaptic changes that parallel long-term memory and changes in behavior.

Epigenetic gene modification has been shown to have very clear effects on the biology of brain processes. Changes in the levels of DNA methylation at specific CpG islands have been linked to genes which regulate the production and release of neurotransmitters and neurotrophic factors. (4) Most notably, hypermethylation of brain-derived neurotrophic factor (BDNF) with the net effect of reducing neurotrophic factors has been reported in several animal and human models of posttraumatic stress disorder (PTSD). For example, in animal models, stress-driven changes in DNA methylation of the BDNF gene has been observed in a rodent model of PTSD. (5)

Epigenetic regulation is crucial for normal brain development, and in addition to changes in the methylation of BDNF, there are a number of other important immune based and hormonal influences as well. Furthermore, there is an abundance of evidence that gene loci are differentially methylated between controls and psychiatric patients. (6) Neurodevelopmental disorders, such as autism, have been demonstrated to involve changes in miRNA expression and DNA methylation in hundreds of common and rare gene variants. (7) Recent studies suggest that schizophrenia may be characterized by aberrant DNA methylation, resulting in a deficit of coordinating epigenetic processes across promoter gene networks. (8) Clinical studies have found that childhood adversity and stressful life events in adulthood increase the risk for major depression. (9) The epigenetic basis for increased vulnerability may be based upon the observation that individuals with major depression exhibit greater DNA methylation and gene repression. (10) In abused suicide completers, the BDNF gene is hypermethylated compared with controls. (11) These results suggest that epigenetic changes in early childhood may significantly contribute to the neuropathology of depression by reducing the activity of neurotrophic factors.

While the importance of DNA methylation during development is well established, the role of DNA methylation-demethylation in the adult brain has only recently become appreciated in several pathological states, including drug addiction and PTSD. There are even some studies which suggest that epigenetic modifications can be transmitted to offspring, which raises the possibility that behavioral experience in adult life might influence gene expression in subsequent generations, a controversial concept known as transgenerational inheritance. Researchers have shown that higher levels of good maternal care cause the female offspring to show the same high-quality care toward their own offspring, validating the idea that behavioral phenotypes are socially transmitted from generation to generation through genetic factors that modify particular CpG islands. (12) Changes in the methylation status at a single CpG site in the glucocorticoid receptor have been linked to maternal grooming behavior in animals across generations. (13) In humans, the September 11 terrorist attacks in New York saw the detection of lower cortisol levels in the 1-yearold offspring who were gestating in utero at the time that their mothers witnessed the attacks, again demonstrating the profound effects of experience on gene expression. (14)

From a therapeutic perspective, both pharmacological and nonpharmacological modulations of gene expression have been shown to have potential efficacy in a variety of psychiatric disorders. Propionic acid, a major short-chain fatty acid produced by gastrointestinal bacteria such as Clostridia, can produce reversible behavioral and epigenetic changes closely resembling those found in autism when administered to rodents. (15) Cruciferous vegetables such as kale, cabbage, brussels sprouts, and broccoli sprouts contain chemical components, such as sulforaphane (SFN) and indole-3-carbinol (I3C), which have been revealed to be regulators of microRNAs (miRNAs) and inhibitors of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). (16) Zimmerman et al. conducted a placebo-controlled, double-blind, randomized trial in which young men (aged 13-27) with moderate to severe autism received the phytochemical sulforaphane (n = 29) derived from broccoli sprout extracts or indistinguishable placebo (n = 15). The group receiving sulforaphane showed substantial declines (improvement of behavior). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication. Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. (17) These studies provide evidence that natural products which modify gene expression may have therapeutic efficacy in psychiatric disorders such as autism.

Several pharmacological and nonpharmacological epigenetic regulators have also been shown to exert antidepressant effects via inhibition of histone deacetylases. (18) Epigenetic regulation of type-2 metabotropic glutamate (mGluR2) receptors have recently been linked to antidepressant efficacy. Acetylcarnitine was found to have a rapid and enduring antidepressant effect on rats via promoting transcription of the mGlu2 receptor gene in the hippocampus and prefrontal cortex. L-acetylcarnitine promotes acetylation of histones and can induce mGlu2 receptor expression by increasing its acetylation. (19) Valproic acid, a drug approved for epilepsy and bipolar disorders, is a histone deacetylase inhibitor. Epigenetic drugs such as sodium butyrate show antidepressantlike effects in preclinical studies, and their efficacy is proposed to be mediated by facilitating demethylation and thereby enhancing specific expression of key genes involved in mood or memory. For example, an antidepressantlike effect of sodium butyrate has been demonstrated to be associated with an increase in BDNF gene expression. (20) These observations suggest that novel antidepressants which can favorably alter BDNF expression through epigenetic mechanisms should be further clinically assessed.

There is a growing interest in methylation disturbances and risk of depression. Nonpharmacologically, DNA methylation is accomplished through metabolism of methyl donors such as folate, vitamin B12, methionine, betaine (trimethylglycine), and choline. Diagnostically, several clinical labs are assessing specific DNA regions for use in psychiatric disorders. Methylenetetrahydrofolate reductase (MTHFR) genetic variation has been associated with vulnerability to certain psychiatric disorders, including depression. In one study, depression symptom severity varied by C677T genotype, with 677CC genotype showing the most severe symptom severity course over the 60 months of observation. (21) In a double-blind, randomized, placebo-controlled trial, patients with SSRI-resistant MDD received L-methylfolate 15 mg/d for 60 days, placebo for 30 days followed by L-methylfolate 15 mg/d for 30 days, or placebo for 60 days. (22) The effects of baseline levels of select biological and genetic markers individually and combined on treatment response to L-methylfolate versus placebo were evaluated; genetic markers related to disturbed methylation pathways predicted significantly (p [less than or equal to] .05) greater reductions in depression scores with L-methylfolate versus placebo. (23)

Variation in the serotonin transporter gene (referred to as SERT or SLC6A4) has been suggested to impart differences in antidepressant treatment response. In one study, clinical response to treatment with escitalopram, an SSRI antidepressant, was assessed by changes of HAM-D scores after 6 weeks of treatment. Lower average methylation was seen across multiple CpG sites of the serotonin transporter, suggesting that DNA hypomethylation may increase serotonin transporter expression and thereby decrease serotonin availability and SSRI efficacy. (24)

In conclusion, an advance in our understanding of how changes in gene expression based upon environmental exposure influence brain development is a promising opportunity for preventive therapeutics in psychiatry. (25) The awareness that adverse child experiences can irreversibly modify the developing brain should give renewed urgency and attention to these effects, which can no longer be regarded as strictly psychological. In autism, preliminary evidence suggests that alterations in the gut microbiome can change the expression of gene pathways and that dietary interventions may favorably alter the disease trajectory. In PTSD, epigenetic changes of cortisol and BDNF regulatory sites offer exciting new opportunities to discover novel therapeutic agents that can modify the abnormal consolidation of memories related to trauma. Finally, in depression and schizophrenia, our understanding that key hypomethylated sites of gene expression offers us exciting new opportunities to target these disturbances with methyl-based dietary supplements.

Notes

(1.) Jabbari K, Bernardi G. "Cytosine methylation and CpG, TpG (CpA) and TpA frequencies. Gene. 2003;333:143-149.

(2.) Klengel T, Binder EB. Epigenetics of stress-related psychiatric disorders and gene x environment interactions. Neuron. 2015;86(6):1343-1357.

(3.) Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009;10:295-304

(4.) Grayson D, Guidotti A. The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology. 2013;38(1):138-166.

(5.) Roth TL, Zoladz PR, Sweatt JD, Diamond DM. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder. I Psychiatr Res. 2011 Jul;45(7):919-926.

(6.) Grayson & Guidotti. 2013. Op cit.

(7.) De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014 November;515(7526):209-215.

(8.) Akbarian S. Epigenetic mechanisms in schizophrenia. Dialogues Clin Neurosci. 2014 Sep;16(3):405-417.

(9.) McCrory E, De Brito SA, Viding E. The link between child abuse and psychopathology: a review of neurobiological and genetic research. I R Soc Med. 2012 Apr; 105(4): 151-156.

(10.) Davies M, Krause L, Bell J, et al. Hypermethylation in the ZBTB20 gene is associated with major depressive disorder. Genome Biol. 2014 Apr 2;15(4):R56.

(11.) Haghighi F, Xin Y, Chanrion B, et al. Increased DNA methylation in the suicide brain. Dialogues Clin Neurosci. 2014 Sep;16(3):430-438.

(12.) Dias B, Ressler K Experimental evidence needed to demonstrate inter- and trans-generational effects of ancestral experiences in mammals. Bioessays. 2014 Oct;36(10): :919-923.

(13.) Yehuda R, Flory JD, Bierer LM, et al. Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder. Biol Psychiatry. 2015 Feb 15;77(4):356-364.

(14.) Dias B, Ressler, K Experimental evidence needed to demonstrate inter- and trans-generational effects of ancestral experiences in mammals. Bioessays. 2014 Oct;36(10):919-923.

(15.) MacFabe DF. Enteric short-chain fatty acids: microbial messengers of metabolism, mitochondria, and mind: implications in autism spectrum disorders. Microh Ecol Health Dis. 2015 May 29;26:28177.

(16.) Vahid F, Zand H, Nosrat-Mirshekarlou E, Najafi R, Hekmatdoost A. The role dietary of bioactive compounds on the regulation of histone acetylases and deacetylases: a review. Gene. 2015 May 10;562(1):8-15.

(17.) Singh K, Connors SL, Macklin EA, et al. Sulforaphane treatment of autism spectrum disorder (ASD). Proc Natl Acad Sci USA. 2014 Oct 28;111 (43):15550-15555.

(18.) Fuchikami M, Yamamoto S, Morinobu S, Okada S, Yamawaki Y, Yamawaki S. The potential use of histone deacetylase inhibitors in the treatment of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2015 Mar 25.

(19.) Cuccurazzu B, Bortolotto V, Valente MM, et al. Upregulation of mGlu2 receptors via NF-[kappa]B p65 acetylation is involved in the Proneurogenic and antidepressant effects of acetyl-L-carnitine. Neuropsychopharmacology. 2013 Oct;38(11):2220-2230.

(20.) Wei Y, Melas PA, Wegener G, Mathe AA, Lavebratt C. Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene. Int J Neuropsychopharmacol. 2014 Oct 31; 18(2).

(21.) Bousman CA, Potiriadis M, Everall IP, Gunn JM. Methylenetetrahydrofolate reductase (MTHFR) genetic variation and major depressive disorder prognosis: A five-year prospective cohort study of primary care attendees. Am J Med Genet B Neuropsychiatr Genet. 2014 Jan;165B(1):68-76.

(22.) Papakostas Gl, Shelton RC, Zajecka JM, et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. I Clin Psychiatry. 2014 Aug;75(8):855-863.

(23.) Ibid.

(24.) Domschke K, Tidow N, Schwarte K, et al. Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response. Int J Neuropsychopharmacol 2014 Aug;17(8):1167-1176.

(25.) Sharma RP, Gavin DP, Grayson DR. CpG methylation in neurons: message, memory, or mask? Neuropsychopharmacology. 2010 Sep;35(10):2009-2020.

Dr. Jay Lombard is Co-founder and Chief Scientific Officer and Medical Director at Genomind. He is responsible for Genomind's scientific research and development, as well as medical leadership and clinical oversight. Dr. Lombard is a board certified neurologist. Dr. Lombard has published several books on the role of nutrition and the brain and has lectured extensively on this topic. He has had numerous television and radio appearances including appearances on Larry King, Dr. Oz, CBS News, Fox News, The Early Morning Show and others. He was also invited to present at TEDMED 2012.

Prior to founding Genomind, Dr. Lombard served as the chief of Neurology at Bronx Lebanon Hospital where he led the Stroke Unit. He is also a former clinical assistant professor of neurology at New York Presbyterian Hospital, clinical instructor of Neurology and Medicine at Albert Einstein College of Medicine, and chief of Neurology at Westchester Square Medical Center and the Brain Behavior Center.

Dr. Lombard is a graduate of Nova Southeastern University College of Osteopathic Medicine. He combined his psychiatry and neurology residency training at Long Island Jewish Medical Center in New York.
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Date:Oct 1, 2015
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