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Epigenetic mechanism of SETDB1 in brain: implications for neuropsychiatric disorders.

ABSTRACT: Neuropsychiatric disorders are a collective of cerebral conditions with a multifactorial and polygenetic etiology. Dysregulation of epigenetic profiles in the brain is considered to play a critical role in the development of neuropsychiatric disorders. SET domain, bifurcate 1 (SETDB1), functioning as a histone H3K9 specific methyltransferase, is not only critically involved in transcriptional silencing and local heterochromatin formation, but also affects genome-wide neuronal epigenetic profiles and is essential for 3D genome integrity. Here, we provide a review of recent advances towards understanding the role of SETDB1 in the central nervous system during early neurodevelopment as well as in the adult brain, with a particular focus on studies that link its functions to neuropsychiatric disorders and related behavioral changes, and the exploration of novel therapeutic strategies targeting SETDB1.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC7176658 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Epigenetic mechanism of SETDB1 in brain: implications for neuropsychiatric disorders.

Zhu Yueyan Y Sun Daijing D Jakovcevski Mira M Jiang Yan Y

Translational psychiatry 20200422 1

Neuropsychiatric disorders are a collective of cerebral conditions with a multifactorial and polygenetic etiology. Dysregulation of epigenetic profiles in the brain is considered to play a critical role in the development of neuropsychiatric disorders. SET domain, bifurcate 1 (SETDB1), functioning as a histone H3K9 specific methyltransferase, is not only critically involved in transcriptional silencing and local heterochromatin formation, but also affects genome-wide neuronal epigenetic profiles ...[more]

PMID: 32321908

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Project description:Melatonin, the primary indoleamine hormone of the mammalian pineal gland, is known to have a plethora of neuroregulatory, neuroprotective and other properties. Melatonergic signalling is mediated by its two GPCRs, MT1 and MT2 , which are widely expressed in the mammalian CNS. Melatonin levels and receptor expression often show a decrease during normal ageing, and this reduction may be accelerated in some disease states. Depleted melatonergic signalling has been associated with neuropsychiatric dysfunction and impairments in cognition, memory, neurogenesis and neurorestorative processes. The anticonvulsant and mood stabilizer, valproic acid (VPA), up-regulates melatonin MT1 and/or MT2 receptor expression in cultured cells and in the rat brain. VPA is known to affect gene expression through several mechanisms, including the modulation of intracellular kinase pathways and transcription factors, as well as the inhibition of histone deacetylase (HDAC) activity. Interestingly, other HDAC inhibitors, such as trichostatin A, which are structurally distinct from VPA, can also up-regulate melatonin receptor expression, unlike a VPA analogue, valpromide, which lacks HDAC inhibitory activity. Moreover, VPA increases histone H3 acetylation along the length of the MT1 gene promoter in rat C6 cells. These findings indicate that an epigenetic mechanism, linked to histone hyperacetylation/chromatin remodelling and associated changes in gene transcription, is involved in the up-regulation of melatonin receptors by VPA. Epigenetic induction of MT1 and/or MT2 receptor expression, in areas where these receptors are lost because of ageing, injury or disease, may be a promising therapeutic avenue for the management of CNS dysfunction and other disorders. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.

Dataset Information

Epigenetic mechanism of SETDB1 in brain: implications for neuropsychiatric disorders.

Publications

Epigenetic mechanism of SETDB1 in brain: implications for neuropsychiatric disorders.

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