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miR-383-5p Regulated by the Transcription Factor CTCF Affects Neuronal Impairment in Cerebral Ischemia by Mediating Deacetylase HDAC9 Activity

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Abstract

Stroke, the leading cause of long-term disability worldwide, is caused by the blockage or hemorage of cerebral arteries. The resultant cerebral ischemia causes local neuronal death and brain injury. Histone deacetylase 9 (HDAC9) has been reported to be elevated in ischemic brain injury, but its mechanism in stroke is still enigmatic. The present study aimed to unveil the manner of regulation of HDAC9 expression and the effect of HDAC9 activation on neuronal function in cerebral ischemia. MicroRNAs (miRNAs) targeting HDAC9 were predicted utilizing bioinformatics analysis. We then constructed the oxygen glucose deprivation (OGD) cell model and the middle cerebral artery occlusion (MCAO) rat model, and elucidated the expression of CCCTC binding factor (CTCF)/miR-383-5p/HDAC9. Targeting between miR-383-5p and HDAC9 was verified by dual-luciferase reporter assay and RNAi. After conducting an overexpression/knockdown assay, we assessed neuronal impairment and brain injury. We found that CTCF inhibited miR-383-5p expression via its enrichment in the promoter region of miR-383-5p, whereas the miR-383-5p targeted and inhibited HDAC9 expression. In the OGD model and the MCAO model, we confirmed that elevation of HDAC9 regulated by the CTCF/miR-383-5p/HDAC9 pathway mediated apoptosis induced by endoplasmic reticulum stress, while reduction of HDAC9 alleviated apoptosis and the symptoms of cerebral infarction in MCAO rats. Thus, the CTCF/miR-383-5p/HDAC9 pathway may present a target for drug development against ischemic brain injury.

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Data Availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

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Author notes

  1. Jun Shen, Qiu Han and Wangjun Li contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Soochow University, No.188, Shizi Road, Suzhou, 215006, People’s Republic of China

    Jun Shen & Shouru Xue

  2. Department of Neurology, The Affiliated Huai’an Hospital of Xuzhou Medical University & The Second People’s Hospital of Huai’an, Huai’an, 223302, People’s Republic of China

    Jun Shen & Jingmin Lu

  3. Department of Neurology, Huai’an First People’s Hospital & The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, Huai’an, 223300, People’s Republic of China

    Qiu Han

  4. Department of Neurology, Changshu No. 2 People’s Hospital (The 5th Clinical Medical College of Yangzhou University), Changshu, 215501, People’s Republic of China

    Wangjun Li

  5. Department of Neurology, Hongze Huai’an District People’s Hospital, No. 102, Huai’an, 223100, People’s Republic of China

    Xiaochang Chen

  6. Department of Neurosurgery, The Affiliated Huai’an Hospital of Xuzhou Medical University & The Second People’s Hospital of Huai’an, Huai’an, 223302, People’s Republic of China

    Jinyu Zheng

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  1. Jun Shen
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Contributions

JS designed the study. QH collated the data. WJL and JML carried out data analyses and produced the initial draft of the manuscript. XCC revised the figures. JYZ and SRX contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.

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Correspondence to Xiaochang Chen or Shouru Xue.

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SUPPLEMENTARY FIGURE 1

(A) Flow cytometry of apoptosis of neurons upon oe-CTCF or si-CTCF treatment. (B) The apoptosis rate detected by flow cytometry upon sh-CTCF or miR-383-5p inhibitpr treatment. (PNG 336 kb)

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Shen, J., Han, Q., Li, W. et al. miR-383-5p Regulated by the Transcription Factor CTCF Affects Neuronal Impairment in Cerebral Ischemia by Mediating Deacetylase HDAC9 Activity. Mol Neurobiol 59, 6307–6320 (2022). https://doi.org/10.1007/s12035-022-02840-4

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