Abstract
The accumulation of intracellular β-amyloid peptide (Aβ) is important pathological characteristic of Alzheimer's disease (AD). However, the exact underlying molecular mechanism remains to be elucidated. Here, we reported that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1), a long n on-coding RNA, exhibits repressed expression in the early stage of AD and its down-regulation declines neuroglial cell mediating Aβ clearance via inhibiting expression of endocytosis-related genes. We find that NEAT1 is associated with P300/CBP complex and its inhibition affects H3K27 acetylation (H3K27Ac) and H3K27 crotonylation (H3K27Cro) located nearby to the transcription start site of many genes, including endocytosis-related genes. Interestingly, NEAT1 inhibition down-regulates H3K27Ac but up-regulates H3K27Cro through repression of acetyl-CoA generation. NEAT1 also mediates the binding between STAT3 and H3K27Ac but not H3K27Cro. Therefore, the decrease of H3K27Ac and/or the increase of H3K27Cro declines expression of multiple related genes. Collectively, this study first reveals the different roles of H3K27Ac and H3K27Cro in regulation of gene expression and provides the insight of the epigenetic regulatory mechanism of NEAT1 in gene expression and AD pathology.
Keywords:
Alzheimer’s disease; Aβ; Histone modification; NEAT1; P300.
MeSH terms
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Acetyl Coenzyme A / metabolism
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Acetylation / drug effects
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Peptides / pharmacology
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Animals
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Caveolin 2 / antagonists & inhibitors
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Caveolin 2 / genetics
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Caveolin 2 / metabolism
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Disease Models, Animal
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Epigenesis, Genetic
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Gene Expression / drug effects
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Histones / metabolism
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Mice
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Mice, Transgenic
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Neuroglia / cytology
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Neuroglia / metabolism
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Peptide Fragments / metabolism*
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Peptide Fragments / pharmacology
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RNA Interference
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RNA, Long Noncoding / antagonists & inhibitors
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RNA, Long Noncoding / genetics
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RNA, Long Noncoding / metabolism*
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RNA, Small Interfering / metabolism
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Receptor, Transforming Growth Factor-beta Type I / antagonists & inhibitors
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Receptor, Transforming Growth Factor-beta Type I / genetics
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Receptor, Transforming Growth Factor-beta Type I / metabolism
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STAT3 Transcription Factor / metabolism
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Transforming Growth Factor beta2 / antagonists & inhibitors
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Transforming Growth Factor beta2 / genetics
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Transforming Growth Factor beta2 / metabolism
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p300-CBP Transcription Factors / metabolism
Substances
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Amyloid beta-Peptides
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Cav2 protein, mouse
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Caveolin 2
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Histones
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NEAT1 long non-coding RNA, mouse
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Peptide Fragments
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RNA, Long Noncoding
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RNA, Small Interfering
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STAT3 Transcription Factor
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Tgfb2 protein, mouse
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Transforming Growth Factor beta2
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amyloid beta-protein (1-42)
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Acetyl Coenzyme A
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p300-CBP Transcription Factors
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Receptor, Transforming Growth Factor-beta Type I
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Tgfbr1 protein, mouse