KLF6 facilitates differentiation of odontoblasts through modulating the expression of P21 in vitro

Chen, Zhuo; Wu, Wenzhi; Chen, Zheng; Lan, Yanhua; Xie, Hujun; Xie, Zhijian

doi:10.1038/s41368-022-00172-6

Cited by 5 publications

(2 citation statements)

References 46 publications

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“…2A–H). Besides, as a marker of odontoblast differentiation (Chen et al 2022), the expression of P21 was decreased in cko odontoblasts (Fig. 4Q).…”

Section: Resultsmentioning

confidence: 99%

ASH2L, Core Subunit of H3K4 Methylation Complex, Regulates Amelogenesis

Zhu,

Ma,

Xie

et al. 2023

J Dent Res

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Histone methylation assumes a crucial role in the intricate process of enamel development. Our study has illuminated the substantial prevalence of H3K4me3 distribution, spanning from the cap stage to the late bell stage of dental germs. In order to delve into the role of H3K4me3 modification in amelogenesis and unravel the underlying mechanisms, we performed a conditional knockout of Ash2l, a core subunit essential for the establishment of H3K4me3 within the dental epithelium of mice. The absence of Ash2l resulted in reduced H3K4me3 modification, subsequently leading to abnormal morphology of dental germ at the late bell stage. Notably, knockout of Ash2l resulted in a loss of polarity in ameloblasts and odontoblasts. The proliferation and apoptosis of the inner enamel epithelium cells underwent dysregulation. Moreover, there was a notable reduction in the expression of matrix-related genes, Amelx and Dspp, accompanied with impaired enamel and dentin formation. Cut&Tag-seq (cleavage under targets and tagmentation sequencing) analysis substantiated a reduction of H3K4me3 modification on Shh, Trp63, Sp6, and others in the dental epithelium of Ash2l knockout mice. Validation through real-time polymerase chain reaction, immunohistochemistry, and immunofluorescence consistently affirmed the observed downregulation of Shh and Sp6 in the dental epithelium following Ash2l knockout. Intriguingly, the expression of Trp63 isomers, DNp63 and TAp63, was perturbed in Ash2l defect dental epithelium. Furthermore, the downstream target of TAp63, P21, exhibited aberrant expression within the cervical loop of mandibular first molars and incisors. Collectively, our findings suggest that ASH2L orchestrates the regulation of crucial amelogenesis-associated genes, such as Shh, Trp63, and others, by modulating H3K4me3 modification. Loss of ASH2L and H3K4me3 can lead to aberrant differentiation, proliferation, and apoptosis of the dental epithelium by affecting the expression of Shh, Trp63, and others genes, thereby contributing to the defects of amelogenesis.

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“…2A–H). Besides, as a marker of odontoblast differentiation (Chen et al 2022), the expression of P21 was decreased in cko odontoblasts (Fig. 4Q).…”

Section: Resultsmentioning

confidence: 99%

ASH2L, Core Subunit of H3K4 Methylation Complex, Regulates Amelogenesis

Zhu,

Ma,

Xie

et al. 2023

J Dent Res

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“…KLF6 binds to specific DNA sequences called KLF6 response elements in the promoters of target genes. This regulation of gene expression allows KLF6 to control diverse cellular functions (5,6). KLF6 plays an important role in heart development and participates in the development and progression of cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Wtap-Mediated M6a Modification of Klf6 Aggravates Hypoxia/Reoxygenation-Induced Human Cardiomyocyte Injury

Fang,

Li,

2024

Shock

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Background Myocardial infarction (MI) is a severe condition that typically results from the ischemia and necrosis of heart muscle. Kruppel-like factor 6 (KLF6) can aggravate myocardial ischemia/reperfusion injury. This work aims to reveal its role and mechanism in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury. Methods Human cardiomyocyte (AC16) was exposed to hypoxic treatment to mimic MI-like cell injury. mRNA expression levels of KLF6 and WT1 associated protein (WTAP) were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was detected by western blotting assay. Cell viability was assessed by CCK-8 assay. Cell apoptosis and cell cycle were investigated by flow cytometry. Enzyme-linked immunosorbent assays were conducted to detect IL-1β, TNF-α and IL-6 levels. Fe2+ colorimetric assay kit was used to detect Fe2+ level. MDA Content Assay Kit was used to detect MDA level. Cellular ROS Assay kit was applied to assess ROS level. The association of KLF6 and WTAP was identified by RNA immunoprecipitation assay and dual-luciferase reporter assay. Results KLF6 and WTAP expression at mRNA and protein levels were significantly upregulated in serum samples of MI patients and H/R-induced AC16 cells when compared with control groups. KLF6 silencing attenuated H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress and ferroptosis. Additionally, WTAP stabilized KLF6 mRNA by regulating its m6A modification. Further, WTAP knockdown rescued H/R-induced AC16 cell apoptosis, inflammatory response, oxidative stress and ferroptosis by decreasing KLF6 expression. Conclusion WTAP-mediated m6A modification of KLF6 aggravated hypoxia/reoxygenation-induced apoptosis, inflammatory response, oxidative stress and ferroptosis of human cardiomyocytes, providing a therapeutic strategy for MI.

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