Genomewide alteration of histone H3K4 methylation underlies genetic vulnerability to psychopathology

Nesbit, Nicholas; Wallace, Rachel M.; Harihar, S.; Zhou, Millie; Jung, Jae-Yoon; Silberstein, Micah; Lee, Phil H.

doi:10.1007/s12041-021-01294-2

Cited by 7 publications

(6 citation statements)

References 50 publications

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“…In addition, we found that the TNFAIP3 mRNA level was negatively correlated with the severity of depression and could be used to measure the improvement of depressive symptoms, as assessed by the HAMD-17 score [10]. Some previous work reported that alteration of histone H3K4 methylation underlies the genetic vulnerability to the psychopathology of depression [17]. It has been proposed that downregulation of TNFAIP3 in CD4 + T cells of systemic lupus erythematosus (SLE) patients may be mediated by histone H3K4 demethylation resulting in reduction of H3K4me3 at the TNFAIP3 gene promoter [18].…”

Section: Discussionmentioning

confidence: 75%

Aberrant Histone Modification of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in Major Depressive Disorder

et al. 2023

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Activated toll-like receptor (TLR) signaling has been well investigated in major depressive disorder (MDD).We previously reported that TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 play important roles in regulating the toll-like receptor 4 (TLR4) signaling pathway and may serve as novel targets in the pathogenesis of MDD. Recently, aberrant histone modi cation has been implicated in several psychiatric disorders, including schizophrenia and mood disorder; the most thoroughly studied modi cation is histone 3 lysine 4 tri-methylation (H3K4me3). In this work, we aimed to explore H3K4me3 differences in the promotors of genes encoding the abovementioned factors in patients with MDD, and whether they were altered after antidepressant treatment. A total of 28 MDD patients and 28 healthy controls were recruited. Peripheral blood mononuclear cells (PBMCs) were collected. The levels of H3K4me3 in the promoters of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155were measured through chromatin immunoprecipitation (ChIP) followed by DNA methylation assay. Analysis of covariance was used to evaluate between-group differences after adjusting for age, sex, BMI, and smoking. In comparison with healthy controls, patients with MDD showed signi cantly lower H3K4me3 levels in the promoters of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in PBMCs. These levels were not signi cantly altered after completion of a 4-week antidepressant treatment. To explore the association between depression severity and H3K4me3 levels, a multiple linear regression model was generated. The results revealed that levels of H3K4me3 in the TNIP2 promoters a negative correlation with the 17-item Hamilton Depression Rating Scale (HAND-17) score, whereas that of TLR4 had a positive correlation with this score. The present results suggest that decreased H3K4me3 levels in the promoters of the genes encoding TNFAIP3, TLR4, miR-146a, miR-155, andTNIP2 may be a mechanism underlying the mRNA expression dysregulation reported in MDD patients.

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Section: Discussionmentioning

confidence: 75%

Aberrant Histone Modification of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in Major Depressive Disorder

et al. 2023

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“…The monogenic nature of KMT2F-associated schizophrenia, however, informs the relevance of H3K4 methylation to the pathophysiology of schizophrenia. Furthermore, a genome-wide association study highlighted the link between genetic variants in the H3K4 methylation pathway and schizophrenia status, validating these molecular relations outside of the context of rare damaging variants ( Nesbit et al, 2021 ). H3K4 methylation pattern is tightly linked to human glial cell differentiation ( Shulha et al, 2013 ).…”

Section: Extending the Rdeo Findings To Common Complex Diseasesmentioning

confidence: 89%

Rare diseases of epigenetic origin: Challenges and opportunities

Merrill

Sharma

et al. 2023

Front. Genet.

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Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene–disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.

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“…Histones are the primary protein components of chromatin, a complex of DNA and protein that comprises the nuclear chromosome in eukaryotic cells. The primary function of chromatin is to Gui et al, 2021;Logue et al, 2021;Nesbit et al, 2021).…”

Section: Histone Deacetylasesmentioning

confidence: 99%

“…The cellular distribution of HDACs is variable and their associated functions are broad and poorly understood. Together, HATs and HDACs regulate gene transcription, alterations of which have been described in many psychiatric, neurodegenerative, and systemic diseases (Glavan et al, 2021; Gui et al, 2021; Logue et al, 2021; Nesbit et al, 2021). Dysregulation of HAT and HDACs are associated with many cancers (Glozak & Seto, 2007), and HDAC inhibitors have shown promise in reversing the malignant phenotype in such cancers.…”

Section: Novel Targets and Radiotracersmentioning

confidence: 99%

Beyond monoamines: I. Novel targets and radiotracers for Positron emission tomography imaging in psychiatric disorders

Lopresti

Royse

Mathis

et al. 2022

Journal of Neurochemistry

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With the emergence of positron emission tomography (PET) in the late 1970s, psychiatry had access to a tool capable of non‐invasive assessment of human brain function. Early applications in psychiatry focused on identifying characteristic brain blood flow and metabolic derangements using radiotracers such as [15O]H2O and [18F]FDG. Despite the success of these techniques, it became apparent that more specific probes were needed to understand the neurochemical bases of psychiatric disorders. The first neurochemical PET imaging probes targeted sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. Based on the centrality of monoamine dysfunction in psychiatric disorders and the measured success of monoamine‐enhancing drugs in treating them, the next 30 years witnessed the development of an armamentarium of PET radiopharmaceuticals and imaging methodologies for studying monoamines. Continued development of monoamine‐enhancing drugs over this time however was less successful, realizing only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely paralleled drug development priorities resulting in the development of new PET imaging agents for non‐monoamine targets. Part one of this review will briefly survey novel PET imaging targets with relevance to the field of psychiatry, which include the metabotropic glutamate receptor type 5 (mGluR5), purinergic P2X7 receptor, type 1 cannabinoid receptor (CB1), phosphodiesterase 10A (PDE10A), and describe radiotracers developed for these and other targets that have matured to human subject investigations. Current limitations of the targets and techniques will also be discussed.

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Genomewide alteration of histone H3K4 methylation underlies genetic vulnerability to psychopathology

Cited by 7 publications

References 50 publications

Aberrant Histone Modification of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in Major Depressive Disorder

Aberrant Histone Modification of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in Major Depressive Disorder

Rare diseases of epigenetic origin: Challenges and opportunities

Beyond monoamines: I. Novel targets and radiotracers for Positron emission tomography imaging in psychiatric disorders

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