Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia

Farrelly, Lorna A.; Zheng, Shuangping; Schrode, Nadine; Topol, Aaron; Bhanu, Natarajan V.; Bastle, Ryan M.; Ramakrishnan, Aarthi; Chan, Jackie; Cetin, Bulent; Flaherty, Erin; Shen, Li; Gleason, Kelly; Tamminga, Carol A.; García, Benjamin A.; Li, Haitao; Brennand, Kristen J.; Maze, Ian

doi:10.1038/s41467-022-29922-0

Cited by 21 publications

(10 citation statements)

References 48 publications

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“…Furthermore, BET proteins have also been associated with cognitive dysfunction and neuropsychiatric diseases, such as SUD, FTD, and schizophrenia [ 16 , 153 , 192 ].…”

Section: Discussionmentioning

confidence: 99%

“…Biochemical analysis, including X-ray crystallography, revealed that BRD4 is a H2A.Z acetylation reader. Notably, BRD4 pharmacological inhibition hampered the interaction between H2A.Z acetylation and BRD4, thus improving the transcriptional signature associated with schizophrenia in patient-derived neurons [ 192 ].…”

Section: Involvement Of Bet Proteins In Neuropathological Conditionsmentioning

confidence: 99%

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Bromodomain and Extra-Terminal Proteins in Brain Physiology and Pathology: BET-ing on Epigenetic Regulation

et al. 2023

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BET proteins function as histone code readers of acetylated lysins that determine the positive regulation in transcription of genes involved in cell cycle progression, differentiation, inflammation, and many other pathways. In recent years, thanks to the development of BET inhibitors, interest in this protein family has risen for its relevance in brain development and function. For example, experimental evidence has shown that BET modulation affects neuronal activity and the expression of genes involved in learning and memory. In addition, BET inhibition strongly suppresses molecular pathways related to neuroinflammation. These observations suggest that BET modulation may play a critical role in the onset and during the development of diverse neurodegenerative and neuropsychiatric disorders, such as Alzheimer’s disease, fragile X syndrome, and Rett syndrome. In this review article, we summarize the most recent evidence regarding the involvement of BET proteins in brain physiology and pathology, as well as their pharmacological potential as targets for therapeutic purposes.

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“…Furthermore, BET proteins have also been associated with cognitive dysfunction and neuropsychiatric diseases, such as SUD, FTD, and schizophrenia [ 16 , 153 , 192 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Involvement Of Bet Proteins In Neuropathological Conditionsmentioning

confidence: 99%

Bromodomain and Extra-Terminal Proteins in Brain Physiology and Pathology: BET-ing on Epigenetic Regulation

et al. 2023

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“…Recently, the inhibition of histone acetylation readers from the BET family protein is deliberated to have potential in schizophrenia therapy since the BET family inhibitor, JQ1 improves transcriptional abnormalities in the neurones of schizophrenia patients [ 123 ]. On the other hand, in animal studies, the pharmacological inhibition of the BET family protein during adolescence, induced schizophrenia-like abnormalities in adulthood [ 97 ].…”

Section: Epigenetic Regulation As Therapeutic Targetsmentioning

confidence: 99%

Epigenetic Targets in Schizophrenia Development and Therapy

2023

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Schizophrenia is regarded as a neurodevelopmental disorder with its course progressing throughout life. However, the aetiology and development of schizophrenia are still under investigation. Several data suggest that the dysfunction of epigenetic mechanisms is known to be involved in the pathomechanism of this mental disorder. The present article revised the epigenetic background of schizophrenia based on the data available in online databases (PubMed, Scopus). This paper focused on the role of epigenetic regulation, such as DNA methylation, histone modifications, and interference of non-coding RNAs, in schizophrenia development. The article also reviewed the available data related to epigenetic regulation that may modify the severity of the disease as a possible target for schizophrenia pharmacotherapy. Moreover, the effects of antipsychotics on epigenetic malfunction in schizophrenia are discussed based on preclinical and clinical results. The obtainable data suggest alterations of epigenetic regulation in schizophrenia. Moreover, they also showed the important role of epigenetic modifications in antipsychotic action. There is a need for more data to establish the role of epigenetic mechanisms in schizophrenia therapy. It would be of special interest to find and develop new targets for schizophrenia therapy because patients with schizophrenia could show little or no response to current pharmacotherapy and have treatment-resistant schizophrenia.

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“…Although for a long time the astroglia cells were thought to provide passive structural support, recent data indicate that they are key regulators of neuronal protection, synaptic pruning and maintenance, and network formation, and hence influence memory and learning as well as cognitive functions. As neuronal cells have different subtypes [ 3 ], as shown in Figure 1 , several studies have addressed the epigenetic dysregulation of brain neuronal cells in major mental diseases [ 4 , 5 , 6 , 7 , 8 ]. Recently, it has become increasingly clear that a significant degree of the gene expression patterns and associated epigenetic alterations that define mental diseases originate from the brain’s non-neuronal cells, such as the microglia and astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Alterations of Brain Non-Neuronal Cells in Major Mental Diseases

Abdolmaleky

Martin

Zhou

et al. 2023

Genes

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The tissue-specific expression and epigenetic dysregulation of many genes in cells derived from the postmortem brains of patients have been reported to provide a fundamental biological framework for major mental diseases such as autism, schizophrenia, bipolar disorder, and major depression. However, until recently, the impact of non-neuronal brain cells, which arises due to cell-type-specific alterations, has not been adequately scrutinized; this is because of the absence of techniques that directly evaluate their functionality. With the emergence of single-cell technologies, such as RNA sequencing (RNA-seq) and other novel techniques, various studies have now started to uncover the cell-type-specific expression and DNA methylation regulation of many genes (e.g., TREM2, MECP2, SLC1A2, TGFB2, NTRK2, S100B, KCNJ10, and HMGB1, and several complement genes such as C1q, C3, C3R, and C4) in the non-neuronal brain cells involved in the pathogenesis of mental diseases. Additionally, several lines of experimental evidence indicate that inflammation and inflammation-induced oxidative stress, as well as many insidious/latent infectious elements including the gut microbiome, alter the expression status and the epigenetic landscapes of brain non-neuronal cells. Here, we present supporting evidence highlighting the importance of the contribution of the brain’s non-neuronal cells (in particular, microglia and different types of astrocytes) in the pathogenesis of mental diseases. Furthermore, we also address the potential impacts of the gut microbiome in the dysfunction of enteric and brain glia, as well as astrocytes, which, in turn, may affect neuronal functions in mental disorders. Finally, we present evidence that supports that microbiota transplantations from the affected individuals or mice provoke the corresponding disease-like behavior in the recipient mice, while specific bacterial species may have beneficial effects.

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Chromatin profiling in human neurons reveals aberrant roles for histone acetylation and BET family proteins in schizophrenia

Cited by 21 publications

References 48 publications

Bromodomain and Extra-Terminal Proteins in Brain Physiology and Pathology: BET-ing on Epigenetic Regulation

Bromodomain and Extra-Terminal Proteins in Brain Physiology and Pathology: BET-ing on Epigenetic Regulation

Epigenetic Targets in Schizophrenia Development and Therapy

Epigenetic Alterations of Brain Non-Neuronal Cells in Major Mental Diseases

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