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Abstract: SA-PO1040

Melatonin Increases Survival Through Upregulation of Clock NEAT1 and Enhancer-Associated Histone Modifications in Albumin-Injury Tubular Cells

Session Information

Category: Pathology and Lab Medicine

  • 1800 Pathology and Lab Medicine

Authors

  • Wu, Chia-Chao, Tri-Service General Hospital Department of Internal Medicine, Taipei, Taiwan
  • Lu, Kuo-Cheng, Taipei Tzu Chi Hospital, Taipei, Taiwan
Background

Melatonin modulates circadian rhythm via the core clock genes, thereby regulating numerous physiological conditions in kidneys. The melatonin-regulated coding RNA is highly identified, it remains unknown whether long noncoding RNAs (lncRNAs) can be modulated by melatonin and exhibit the diurnal rhythm in renal tissue.

Methods

We identify melatonin-regulated clock lncRNAs including NEAT1, which are upregulated by melatonin and BMAL1/CLOCK heterodimer in human renal tubular epithelial cells (TECs).

Results

Neat1 oscillations associated nocturnal change of core clock genes and endogenous melatonin in mouse TECs. Clock NEAT1 promote TECs proliferation through an increased occupancy of histone 3 lysine 27 acetylation (H3K27ac) and histone 3 lysine 4 mono-methylation (H3K4me1) levels at MKI67 enhancer regions. Molecular studies showed that melatonin enhanced NEAT1 expression via increasing BMAL1 stability and thereby enrichment on NEAT1 promoter. Treatment of albumin-injured TECs with melatonin alleviated cell death by transactivating clock NEAT1 and restore the reduction levels of H3K4me1, H3K27ac, core clock genes and MKI67. Using an experimental membranous nephropathy (MN) model, exogenous melatonin treatment ameliorates the proteinuria and hypoalbuminaemia in experimental MN kidneys associated with the increased levels of core clock genes, H3K27ac, Mki67 and Neat1 in TECs.

Conclusion

Collectively, our results suggest that melatonin enhanced cell proliferation in albumin-injured TECs via upregulation of clock NEAT1 and NEAT1 mediated-changes in histone modifications and MKI67 levels, which has the potential for therapeutic intervention.

Funding

  • Government Support – Non-U.S.