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 4

Overexpression of Lipin1 in the corpus callosum promotes OPC differentiation and myelination in PWMI mice.

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Overexpression of Lipin1 in the corpus callosum promotes OPC differentia...
(A) Experimental diagram. (B and C) Western blot analysis of Lipin1, CC1, and PDGFR-α levels in the corpus callosum of mice 7 days after stereotaxic injection of lentivirus, with statistical analysis (n = 3). Representative of 3 independent experiments. (D) PA and DG levels in the brain tissue of mice from both groups (n = 6). (E–G) Immunofluorescent staining showing MBP levels in the corpus callosum and striatum of the 3 groups of mice, with statistical analysis (n = 3). Scale bar: 100 μm. (H–J) Immunofluorescence analysis of the number of CC1+ (red) and PDGFR-α+ (green) cells in the corpus callosum 7 days after lentiviral injection, and the ratio of positive cells, with statistical analysis. The high-magnification images are zoomed-in views of the white dashed boxes in the low-magnification images. Scale bars: 100 μm (low magnification) and 25 μm (high magnification). n = 3. Statistics: 1-way ANOVA with LSD post hoc analysis (C, E–G, I, and J). The results are expressed as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. cc, corpus callosum.