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Journal article
Tip60's novel RNA-binding function modulates alternative splicing of pre-mRNA targets implicated in Alzheimer's Disease
The Journal of neuroscience
24 Feb 2023
PMID: 36849418
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 the
brain and this RNA binding function is conserved in human hippocampus and disrupted in
brains 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 in
are 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.
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 in
brains modeling AD pathology and in human AD hippocampus. Importantly, mammalian orthologs of several Tip60-modulated splicing genes in
are 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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Details
- Title
- Tip60's novel RNA-binding function modulates alternative splicing of pre-mRNA targets implicated in Alzheimer's Disease
- Creators
- Akanksha Bhatnagar - Drexel UniversityKeegan Krick - University of PennsylvaniaBhanu Chandra Karisetty - Drexel UniversityEllen M Armour - Drexel UniversityElizabeth A Heller - University of PennsylvaniaFelice Elefant - Department of Biology, Drexel University, Philadelphia, PA 19103, USA fe22@drexel.edu
- Publication Details
- The Journal of neuroscience
- Publisher
- Society for Neuroscience
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Web of Science ID
- WOS:000970978100005
- Scopus ID
- 2-s2.0-85151312918
- Other Identifier
- 991020151064404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences