Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain

Beaver, Mariah; Karisetty, Bhanu Chandra; Zhang, Haolin; Bhatnagar, Akanksha; Armour, Ellen M.; Parmar, Visha; Brown, Reshma; Xiang, Merry; Elefant, Felice

doi:10.1080/15592294.2021.1959742

Cited by 6 publications

(1 citation statement)

References 67 publications

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“…Moreover, we found increased HDAC3 levels, concomitantly with diminished H3 acetylation, in postmortem cortex of AD patients at Braak stages III-IV, which was associated with CDR of 0.5 and very mild dementia (Therriault et al, 2022). Consistent with this study, Drosophila larvae, modeling early human AD neurodegeneration, exhibited enhanced HDAC2 in the brain before Aβ deposition (Beaver et al, 2022). Importantly, we also observed increased HDAC2 and HDAC3 protein levels following AβO treatment in HT22 cells and in APP/PS1 transgenic mice, supporting the importance of targeting class I HDACis in ameliorating cognitive function and preventing neuronal dysfunction.…”

Section: Discussionsupporting

confidence: 89%

Reduction of class I histone deacetylases ameliorates ER‐mitochondria cross‐talk in Alzheimer's disease

et al. 2023

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Several molecular mechanisms have been described in Alzheimer's disease (AD), including repressed gene transcription and mitochondrial and endoplasmic reticulum (ER) dysfunction. In this study, we evaluate the potential efficacy of transcriptional modifications exerted by inhibition or knockdown of class I histone deacetylases (HDACs) in ameliorating ER‐mitochondria cross‐talk in AD models. Data show increased HDAC3 protein levels and decreased acetyl‐H3 in AD human cortex, and increased HDAC2‐3 in MCI peripheral human cells, HT22 mouse hippocampal cells exposed to Aβ1–42 oligomers (AβO) and APP/PS1 mouse hippocampus. Tacedinaline (Tac, a selective class I HDAC inhibitor) counteracted the increase in ER‐Ca2+ retention and mitochondrial Ca2+ accumulation, mitochondrial depolarization and impaired ER‐mitochondria cross‐talk, as observed in 3xTg‐AD mouse hippocampal neurons and AβO‐exposed HT22 cells. We further demonstrated diminished mRNA levels of proteins involved in mitochondrial‐associated ER membranes (MAM) in cells exposed to AβO upon Tac treatment, along with reduction in ER‐mitochondria contacts (MERCS) length. HDAC2 silencing reduced ER‐mitochondria Ca2+ transfer and mitochondrial Ca2+ retention, while knockdown of HDAC3 decreased ER‐Ca2+ accumulation in AβO‐treated cells. APP/PS1 mice treated with Tac (30 mg/kg/day) also showed regulation of mRNA levels of MAM‐related proteins, and reduced Aβ levels. These data demonstrate that Tac normalizes Ca2+ signaling between mitochondria and ER, involving the tethering between the two organelles in AD hippocampal neural cells. Tac‐mediated AD amelioration occurs through the regulation of protein expression at MAM, as observed in AD cells and animal models. Data support transcriptional regulation of ER‐mitochondria communication as a promising target for innovative therapeutics in AD.

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Section: Discussionsupporting

confidence: 89%

Reduction of class I histone deacetylases ameliorates ER‐mitochondria cross‐talk in Alzheimer's disease

et al. 2023

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Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders

et al. 2023

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Tip60's Novel RNA-Binding Function Modulates Alternative Splicing of Pre-mRNA Targets Implicated in Alzheimer's Disease

et al. 2023

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The severity of Alzheimer’s Disease (AD) progression involves a complex interplay of genetics, age, and environmental factors orchestrated by histone acetyltransferase (HAT) mediated neuroepigenetic mechanisms. While disruption of Tip60 HAT action in neural gene control is implicated in AD, alternative mechanisms underlying Tip60 function remain unexplored. Here, we report a novel RNA binding function for Tip60 in addition to its HAT function. We show that Tip60 preferentially interacts with pre-mRNAs emanating from its chromatin neural gene targets in theDrosophilabrain and this RNA binding function is conserved in human hippocampus and disrupted inDrosophilabrains that model AD pathology and in AD patient hippocampus of either sex. Since RNA splicing occurs co-transcriptionally and alternative splicing (AS) defects are implicated in AD, we investigated whether Tip60-RNA targeting modulates splicing decisions and if this function is altered in AD. Replicate multivariate analysis of transcript splicing (rMATS) analysis of RNA-Seq data sets from wild-type and AD fly brains revealed a multitude of mammalian-like AS defects. Strikingly, over half of these altered RNAs identified as bona-fide Tip60-RNA targets that are enriched for in the AD-gene curated database, with some of these AS alterations prevented against by increasing Tip60 in the fly brain. Further, human orthologs of several Tip60-modulated splicing genes inDrosophilaare well characterized aberrantly spliced genes in human AD brains, implicating disruption of Tip60’s splicing function in AD pathogenesis. Our results support a novel RNA interaction and splicing regulatory function for Tip60 that may underly AS impairments that hallmark AD etiology.SIGNIFICANCE:Alzheimer’s Disease (AD) has recently emerged as a hotbed for RNA alternative splicing (AS) defects that alter protein function in the brain yet causes remain unclear. Although recent findings suggest convergence of epigenetics with co-transcriptional AS, whether epigenetic dysregulation in AD pathology underlies AS defects remains unknown. Here we identify a novel RNA interaction and splicing regulatory function for Tip60 histone acetyltransferase that is disrupted inDrosophilabrains modeling AD pathology and in human AD hippocampus. Importantly, mammalian orthologs of several Tip60-modulated splicing genes inDrosophilaare well characterized aberrantly spliced genes in human AD brain. We propose that Tip60 mediated AS modulation is a conserved critical post-transcriptional step that may underlie AS defects now characterized as hallmarks of AD.

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Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain

Cited by 6 publications

References 67 publications

Reduction of class I histone deacetylases ameliorates ER‐mitochondria cross‐talk in Alzheimer's disease

Reduction of class I histone deacetylases ameliorates ER‐mitochondria cross‐talk in Alzheimer's disease

Dissecting the Relationship Between Neuropsychiatric and Neurodegenerative Disorders

Tip60's Novel RNA-Binding Function Modulates Alternative Splicing of Pre-mRNA Targets Implicated in Alzheimer's Disease

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