Tip off the HAT– Epigenetic control of learning and memory by<i>Drosophila</i>Tip60

Xu, Song-Jun; Elefant, Felice

doi:10.1080/19336934.2015.1080887

Cited by 12 publications

(7 citation statements)

References 84 publications

(148 reference statements)

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“…Accordingly, histone deacetylase (HDAC) inhibitors have been proposed as potential procognitive agents for the treatment of AD 891011. Indeed, Tip60 histone acetyltransferase (HAT) in human tau overexpressing Drosophila has been proposed to play a neuroprotective role in impaired cognition during early development of AD 121314. Reciprocally, Drosophila genetic screens have shown that HDAC6 null mutation and pharmacological inhibition can rescue tau-induced microtubule defects in muscles and neurons 15.…”

Section: Introductionmentioning

confidence: 99%

Targeted Downregulation ofkdm4aAmeliorates Tau-engendered Defects inDrosophila melanogaster

2019

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Background Tauopathies, a class of neurodegenerative diseases that includes Alzheimer's disease (AD), are characterized by the deposition of neurofibrillary tangles composed of hyperphosphorylated tau protein in the human brain. As abnormal alterations in histone acetylation and methylation show a cause and effect relationship with AD, we investigated the role of several Jumonji domain-containing histone demethylase ( JHDM ) genes, which have yet to be studied in AD pathology. Methods To examine alterations of several JHDM genes in AD pathology, we performed bioinformatics analyses of JHDM gene expression profiles in brain tissue samples from deceased AD patients. Furthermore, to investigate the possible relationship between alterations in JHDM gene expression profiles and AD pathology in vivo, we examined whether tissue-specific downregulation of JHDM Drosophila homologs ( kdm ) can affect tau R406W -induced neurotoxicity using transgenic flies containing the UAS-Gal4 binary system. Results The expression levels of JHDM1A , JHDM2A/2B , and JHDM3A/3B were significantly higher in postmortem brain tissue from patients with AD than from non-demented controls, whereas JHDM1B mRNA levels were downregulated in the brains of patients with AD. Using transgenic flies, we revealed that knockdown of kdm2 (homolog to human JHDM1 ), kdm3 (homolog to human JHDM2 ), kdm4a (homolog to human JHDM3A ), or kdm4b (homolog to human JHDM3B ) genes in the eye ameliorated the tau R406W -engendered defects, resulting in less severe phenotypes. However, kdm4a knockdown in the central nervous system uniquely ameliorated tau R406W -induced locomotion defects by restoring heterochromatin. Conclusion Our results suggest that downregulation of kdm4a expression may be a potential therapeutic target in AD.

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Section: Introductionmentioning

confidence: 99%

Targeted Downregulation ofkdm4aAmeliorates Tau-engendered Defects inDrosophila melanogaster

2019

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“…We previously demonstrated that Tip60 is required for both MB morphology and function in learning and memory[ 10 , 38 ]. Thus, we first asked whether EE promotes beneficial changes on MB structural morphology and whether this response is dependent upon Tip60 HAT action.…”

Section: Resultsmentioning

confidence: 99%

Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration

Panikker

Iqbal

et al. 2016

PLoS ONE

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Environmental enrichment (EE) conditions have beneficial effects for reinstating cognitive ability in neuropathological disorders like Alzheimer’s disease (AD). While EE benefits involve epigenetic gene control mechanisms that comprise histone acetylation, the histone acetyltransferases (HATs) involved remain largely unknown. Here, we examine a role for Tip60 HAT action in mediating activity- dependent beneficial neuroadaptations to EE using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. We show that flies raised under EE conditions display enhanced MB axonal outgrowth, synaptic marker protein production, histone acetylation induction and transcriptional activation of cognition linked genes when compared to their genotypically identical siblings raised under isolated conditions. Further, these beneficial changes are impaired in both Tip60 HAT mutant flies and APP neurodegenerative flies. While EE conditions provide some beneficial neuroadaptive changes in the APP neurodegenerative fly MB, such positive changes are significantly enhanced by increasing MB Tip60 HAT levels. Our results implicate Tip60 as a critical mediator of EE-induced benefits, and provide broad insights into synergistic behavioral and epigenetic based therapeutic approaches for treatment of cognitive disorder.

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“…Early life exposure to arsenic was found to confer elevated incidence and severity of cancer in childhood and adulthood as supported by a latency period that is decades long . Arsenic-induced epigenetic dysregulation not only gives rise to DNA repair inhibition and cancer progression partly through disrupted gene imprinting, but also leads to the impairment in learning and memory as well as cognitive functions in children and adults after arsenic exposure. , Furthermore, histone acetylation was found to regulate cognitive gene expression by chromatin remodeling in neurons, similar to chromatin decompaction during DNA damage response . Given that TIP60 is abundant in the learning and memory center in the Drosophila brain, and is necessary for mediating axonal outgrowth, our work sets the stage for future studies on the roles of arsenic binding with TIP60 in perturbing the epigenetic patterns in cognitive impairment in human brain after chronic arsenic exposure.…”

Section: Discussionmentioning

confidence: 99%

Arsenite Binds to the Zinc Finger Motif of TIP60 Histone Acetyltransferase and Induces Its Degradation via the 26S Proteasome

Tam

Jiang

Wang

et al. 2017

Chem. Res. Toxicol.

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Arsenic is a ubiquitous environmental contaminant with widespread public health concern. Epidemiological studies have revealed that chronic human exposure to arsenic in drinking water is associated with the prevalence of skin, lung, and bladder cancers. Aberrant histone modifications (e.g., methylation, acetylation, and ubiquitination) were previously found to be accompanied by arsenic exposure; thus, perturbation of epigenetic pathways is thought to contribute to arsenic carcinogenesis. Arsenite is known to interact with zinc finger motifs of proteins, and zinc finger motif is present in and indispensable for the enzymatic activities of crucial histone-modifying enzymes especially the MYST family of histone acetyltransferases (e.g., TIP60). Hence, we reasoned that trivalent arsenic may target the zinc finger motif of these enzymes, disturb their enzymatic activities, and alter histone acetylation. Herein, we found that As3+ could bind directly to the zinc-finger motif of TIP60 in vitro and in cells. In addition, exposure to As3+ could lead to a dose-dependent decrease in TIP60 protein level via the ubiquitin-proteasome pathway. Thus, the results from the present study revealed, for the first time, that arsenite may target cysteine residues in the zinc-finger motif of the TIP60 histone acetyltransferase, thereby altering the H4K16Ac histone epigenetic mark. Our results also shed some new light on the mechanisms underlying the arsenic-induced epigenotoxicity and carcinogenesis in humans.

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Tip off the HAT– Epigenetic control of learning and memory byDrosophilaTip60

Cited by 12 publications

References 84 publications

Targeted Downregulation ofkdm4aAmeliorates Tau-engendered Defects inDrosophila melanogaster

Targeted Downregulation ofkdm4aAmeliorates Tau-engendered Defects inDrosophila melanogaster

Tip60 HAT Action Mediates Environmental Enrichment Induced Cognitive Restoration

Arsenite Binds to the Zinc Finger Motif of TIP60 Histone Acetyltransferase and Induces Its Degradation via the 26S Proteasome

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