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<p>The genetic roles of protein-encoding genes in nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility have been intensively studied, but many gaps remain including the emerging roles of long non-coding RNA. In this study, we found that NSCL/P risk-associated SNPs may have higher chances to modulate lncRNA genes than protein-coding genes. Through a multi-omics screen strategy, we identified a variant in <i>lncPSMB1</i>, associated with the risk of NSCL/P. We found that the rs4710839 risk C allele recruited more MYC, and increased the expression of <i>lncPSMB1</i>. <i>LncPSMB1</i> overexpression zebrafish models caused oedema around the heart and craniofacial defects, compared with control embryos. In vitro experiments, RNA sequencing and enrichment analysis showed that <i>lncPSMB1</i> activated the apoptosis pathway in human embryonic palatal mesenchyme cells. Furthermore, RNA pull-down and RIP (RNA immunoprecipitation) assays demonstrated that <i>lncPSMB1</i> directly bound to KRT1, reduced its protein stability, and promoted ubiquitination-mediated degradation. Meanwhile, knockdown of <i>KRT1</i> significantly rescued <i>lncPSMB1</i> overexpression phenotype by inducing decrease in cell apoptosis and increase in cell proliferation. These findings suggested that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting NSCL/P development.</p><p></p>

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Genetic modulation of lncPSMB1 confers non-syndromic cleft lip with or without cleft palate susceptibility by promoting cell apoptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月29日

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  • Xiaofeng Li,
  • Yue Gao,
  • Tingting Cheng,
  • Junyan Lin,
  • Shu Lou,
  • Lin Wang,
  • Congbo Mi,
  • Xu Ding,
  • Mulong Du,
  • Yongchu Pan

摘要

The genetic roles of protein-encoding genes in nonsyndromic cleft lip with or without cleft palate (NSCL/P) susceptibility have been intensively studied, but many gaps remain including the emerging roles of long non-coding RNA. In this study, we found that NSCL/P risk-associated SNPs may have higher chances to modulate lncRNA genes than protein-coding genes. Through a multi-omics screen strategy, we identified a variant in lncPSMB1, associated with the risk of NSCL/P. We found that the rs4710839 risk C allele recruited more MYC, and increased the expression of lncPSMB1. LncPSMB1 overexpression zebrafish models caused oedema around the heart and craniofacial defects, compared with control embryos. In vitro experiments, RNA sequencing and enrichment analysis showed that lncPSMB1 activated the apoptosis pathway in human embryonic palatal mesenchyme cells. Furthermore, RNA pull-down and RIP (RNA immunoprecipitation) assays demonstrated that lncPSMB1 directly bound to KRT1, reduced its protein stability, and promoted ubiquitination-mediated degradation. Meanwhile, knockdown of KRT1 significantly rescued lncPSMB1 overexpression phenotype by inducing decrease in cell apoptosis and increase in cell proliferation. These findings suggested that modulating lncRNA expression is an important mechanism for risk-associated SNPs in promoting NSCL/P development.