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 3

Reduced Lipin1 expression in the corpus callosum impairs OPC differentiation and myelination.

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Reduced Lipin1 expression in the corpus callosum impairs OPC differentia...
(A) Experimental diagram. (B) Stereotaxic injection coordinates and infection area map of corpus callosum. Scale bar: 100 μm. (C and D) Western blot and statistical analysis of Lipin1, MBP, CC1, and PDGFR-α levels in the corpus callosum of C57BL/6J mice 7 days after stereotaxic injection of lentivirus (n = 3). Representative of 3 independent experiments. (E) PA and DG levels in the brain tissue of mice from both groups (n = 6). (F–H) MBP levels in the corpus callosum (cc) and striatum of C57BL/6J mice 7 days after stereotactic lentivirus injection were detected by immunofluorescent staining and statistically analyzed. Scale bar: 100 μm. (I and J) Statistical analysis of the CC1+/PDGFR-α+ (red/green) cell ratio and positive cells in the corpus callosum of C57BL/6J mice 7 days after stereotactic lentivirus injection was performed using immunofluorescent staining. Scale bars: 100 μm (low magnification) and 25 μm (high magnification). n = 3. (K) Two sets of TEM images of the myelin sheath in the corpus callosum. The high-magnification images are zoomed-in views of the red boxes in the low-magnification images. Scale bars: 1 μm (low magnification) and 200 nm (high magnification). (L and M) G-ratio distribution chart and statistical chart. (N) Percentage plot showing the number of myelinated axons. The number of myelinated axons evaluated was n = 50 per mouse, with 3 mice per group. Statistics: 2-tailed Student’s t test (D, E, G, H, J, M, and N). The results are expressed as mean ± SEM. *P < 0.05; **P < 0.01.