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NEAT1 通过对细胞内吞相关基因表达的表观遗传调控来调节神经胶质细胞介导的 Aβ 清除。

NEAT1 regulates neuroglial cell mediating Aβ clearance via the epigenetic regulation of endocytosis-related genes expression.

机构信息

School of Life Sciences, Tsinghua University, Beijing, 100084, China.

Key Laboratory in Health Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, China.

出版信息

Cell Mol Life Sci. 2019 Aug;76(15):3005-3018. doi: 10.1007/s00018-019-03074-9. Epub 2019 Apr 20.

DOI:10.1007/s00018-019-03074-9
PMID:31006037
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6647258/
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.

摘要

细胞内β-淀粉样肽（Aβ）的积累是阿尔茨海默病（AD）的重要病理特征。然而，其确切的潜在分子机制仍有待阐明。在这里，我们报道核小体旁核斑组装转录本 1（NEAT1），一种长非编码 RNA，在 AD 的早期阶段表现出受抑制的表达，其下调会通过抑制内吞作用相关基因的表达来降低神经胶质细胞介导的 Aβ清除。我们发现 NEAT1 与 P300/CBP 复合物相关，其抑制作用会影响 H3K27 乙酰化（H3K27Ac）和 H3K27 巴豆酰化（H3K27Cro），这两种修饰均位于许多基因的转录起始位点附近，包括内吞作用相关基因。有趣的是，NEAT1 抑制通过抑制乙酰辅酶 A 的产生，下调 H3K27Ac 但上调 H3K27Cro。NEAT1 还介导 STAT3 与 H3K27Ac 之间的结合，但不与 H3K27Cro 结合。因此，H3K27Ac 的减少和/或 H3K27Cro 的增加会降低多个相关基因的表达。总的来说，这项研究首次揭示了 H3K27Ac 和 H3K27Cro 在基因表达调控中的不同作用，并为 NEAT1 在基因表达和 AD 病理中的表观遗传调控机制提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/565a2601848c/18_2019_3074_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/3723e4f51349/18_2019_3074_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/fce2e32048f7/18_2019_3074_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/960813329a20/18_2019_3074_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/aa163d00ebf9/18_2019_3074_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/7c737e64a345/18_2019_3074_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/d1c4113ddf64/18_2019_3074_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/8e502aa1b86c/18_2019_3074_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/565a2601848c/18_2019_3074_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/3723e4f51349/18_2019_3074_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/fce2e32048f7/18_2019_3074_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/960813329a20/18_2019_3074_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/aa163d00ebf9/18_2019_3074_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/7c737e64a345/18_2019_3074_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/d1c4113ddf64/18_2019_3074_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/8e502aa1b86c/18_2019_3074_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a0f1/11105375/565a2601848c/18_2019_3074_Fig8_HTML.jpg

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[4]
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[5]
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[7]
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本文引用的文献

[1]
Functional Domains of NEAT1 Architectural lncRNA Induce Paraspeckle Assembly through Phase Separation.

Mol Cell. 2018-6-21

[2]
The long non-coding RNA NEAT1 enhances epithelial-to-mesenchymal transition and chemoresistance via the miR-34a/c-Met axis in renal cell carcinoma.

Oncotarget. 2017-5-10

[3]
Oct4 transcriptionally regulates the expression of long non-coding RNAs NEAT1 and MALAT1 to promote lung cancer progression.

Mol Cancer. 2017-6-14

[4]
NEAT1/miR-181c Regulates Osteopontin (OPN)-Mediated Synoviocyte Proliferation in Osteoarthritis.

J Cell Biochem. 2017-11

[5]
The Long Noncoding RNA NEAT1 Exerts Antihantaviral Effects by Acting as Positive Feedback for RIG-I Signaling.

J Virol. 2017-4-13

[6]
Long non-coding RNA NEAT1 regulates permeability of the blood-tumor barrier via miR-181d-5p-mediated expression changes in ZO-1, occludin, and claudin-5.

Biochim Biophys Acta Mol Basis Dis. 2017-2-7

[7]
The long non-coding RNA NEAT1 interacted with miR-101 modulates breast cancer growth by targeting EZH2.

Arch Biochem Biophys. 2017-2-1

[8]
NEAT1 modulates herpes simplex virus-1 replication by regulating viral gene transcription.

Cell Mol Life Sci. 2017-3

[9]
Identification of the long noncoding RNA NEAT1 as a novel inflammatory regulator acting through MAPK pathway in human lupus.

J Autoimmun. 2016-7-29

[10]
Mechanisms of Aβ Clearance and Degradation by Glial Cells.

Front Aging Neurosci. 2016-7-5

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