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

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Abstract

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 modification has been implicated in several psychiatric disorders, including schizophrenia and mood disorder; the most thoroughly studied modification 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 30 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-155 were 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 significantly lower H3K4me3 levels in the promoters of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in PBMCs. These levels were not significantly 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, and TNIP2 are involved in psychopathology of major depressive disorder.

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Data Availability

Medical information for these participants is protected, so only processed de-identified data will be made available upon receipt of reasonable request to the corresponding author.

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Acknowledgements

We thank Ya-Ling Huang for excellent experiment support.

Funding

This study was supported by CMRPGTM0021 grants from Kaohsiung Chang Gung Memorial Hospital, Taiwan and by the 111–2314-B-182A-025 -MY3 grants from the National Science and Technology Council, Taiwan.

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Author notes

  1. Chu-Chiao Tseng and Shao-Cheng Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Chu-Chiao Tseng & Yi-Yung Hung

  2. Department of Psychiatry, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, 33004, Taiwan

    Shao-Cheng Wang

  3. Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA

    Shao-Cheng Wang

  4. Department of Nurse-Midwifery and Women Health, National Taipei University of Nursing and Health Sciences, Taipei, 112, Taiwan

    Shao-Cheng Wang

  5. Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan

    Yi-Chien Yang

  6. Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 833, Taiwan

    Hung-Chun Fu & Hong-Yo Kang

  7. Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University, Kaohsiung, 833, Taiwan

    Chen-Kai Chou

  8. Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung, 833, Taiwan

    Chen-Kai Chou & Hong-Yo Kang

  9. Department of Psychiatry, Kaohsiung Municipal Feng Shan Hospital - Under the management of Chang Gung Medical Foundation, Kaohsiung, Taiwan

    Yi-Yung Hung

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  1. Chu-Chiao Tseng
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Contributions

Y.-Y.H. and S.-C.W. designed the study and enrolled patients. Y.-Y.H. and C.-C.T. and analyzed data. Y.-Y.H. and C.-C.T. wrote the manuscript. Y.-C.Y., H.-C.F., C.-K.C., H.-Y.K. consulted and supported the performance and evaluation of chromatin immunoprecipitation. All authors read and edited the manuscript, and approved the final version.

Corresponding author

Correspondence to Yi-Yung Hung.

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Tseng, CC., Wang, SC., Yang, YC. et al. Aberrant Histone Modification of TNFAIP3, TLR4, TNIP2, miR-146a, and miR-155 in Major Depressive Disorder. Mol Neurobiol 60, 4753–4760 (2023). https://doi.org/10.1007/s12035-023-03374-z

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