NAT10-mediated ac4C modification of Lipin1 mRNA contributes to the pathogenesis of PWMI
Xinyu Li, Meng Zhang, Yanan Liu, Chunjie Guo, Yiwei Liu, Lei Han, Zhaowei Feng, Xiue Wei, Ruiqin Yao
Xinyu Li, Meng Zhang, Yanan Liu, Chunjie Guo, Yiwei Liu, Lei Han, Zhaowei Feng, Xiue Wei, Ruiqin Yao
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Research Article Cell biology Neuroscience

NAT10-mediated ac4C modification of Lipin1 mRNA contributes to the pathogenesis of PWMI

Abstract

Preterm white matter injury (PWMI) is a leading cause of cerebral palsy and chronic neurological disabilities in premature infants. It is characterized by defects in oligodendrocyte precursor cell (OPC) differentiation and dysmyelination. Currently, there are no effective therapeutic strategies available in clinical practice. Lipid homeostasis plays a crucial role in myelin development, yet the function of Lipin1 — a key phosphatidic acid phosphatase involved in phospholipid synthesis — remains unclear. In this study, we identified a significant downregulation of Lipin1 in OPCs from PWMI mice, which impaired OPC differentiation and myelin formation. Conversely, Lipin1 overexpression in these mice promoted OPC maturation and enhanced myelin development. We found evidence that N-acetyltransferase 10 (NAT10) acts as a regulator of Lipin1 expression through RNA pull-down and mass spectrometry. NAT10-mediated N4-acetylcytidine (ac4C) modification enhanced Lipin1 mRNA stability and translation, and NAT10 knockdown in OPCs impaired myelination, highlighting its crucial role in Lipin1-mediated myelination. Our study revealed that the downregulation of Lipin1 impaired OPC differentiation and myelination in PWMI, with NAT10-mediated ac4C modification playing a critical role in regulating Lipin1 expression. These findings highlight Lipin1 and NAT10 as promising therapeutic targets for treating myelination defects in PWMI, warranting further investigation into their potential in preterm birth–related neurological disorders.

Authors

Xinyu Li, Meng Zhang, Yanan Liu, Chunjie Guo, Yiwei Liu, Lei Han, Zhaowei Feng, Xiue Wei, Ruiqin Yao

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Figure 2

Reduced expression of Lipin1 in the OPCs of PWMI mice.

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Reduced expression of Lipin1 in the OPCs of PWMI mice. (A) Experimental ...
(A) Experimental diagram. (B and C) Western blot analysis was conducted to detect changes in Lipin1 levels in the corpus callosum of mice from both groups at different time points. NC, negative control (sample incubated with secondary antibody only, no primary antibody), confirming the specificity of the Lipin1 signal. Statistical analysis was performed (n = 3). Representative of 3 independent experiments. (D) PA and DG levels in the brain tissue of mice from 2 groups (n = 6). (E and F) Lipin1 levels (green) in oligodendrocytes (Olig2, red) at different time points were detected by immunofluorescent staining, followed by statistical analysis (n = 3). Scale bars: 100 μm (low magnification) and 25 μm (high magnification). (G and H) mRNA levels of Lipin1 in the P3+3 and P3+14 corpus callosum of 2 groups of mice (n = 5). (I and J) Western blot analysis of Lipin1 levels in primary OPCs from control and OGD groups of mice, followed by statistical analysis (n = 3). Representative of 3 independent experiments. Statistics: 2-tailed Student’s t test (C, D, and F–H) and 1-way ANOVA with LSD post hoc analysis (J). The results are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001.