1. Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation.
- Author
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Li Z, Lui KN, Lau ST, Lai FP, Li P, Chung PH, Wong KK, Tam PK, Garica-Barcelo MM, Hui CC, Sham PC, and Ngan ES
- Subjects
- Humans, Neural Crest metabolism, Transcriptome, Oxidative Phosphorylation, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Polypyrimidine Tract-Binding Protein genetics, Hirschsprung Disease genetics, Hirschsprung Disease metabolism, Enteric Nervous System
- Abstract
Hirschsprung disease is characterized by the absence of enteric neurons caused by the defects of enteric neural crest cells, leading to intestinal obstruction. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis, we identify a gene set of 118 genes commonly dysregulated in all patient enteric neural crest cells, and suggest HDAC1 may be a key regulator of these genes. Furthermore, upregulation of RNA splicing mediators and enhanced alternative splicing events are associated with severe form of Hirschsprung. In particular, the higher inclusion rate of exon 9 in PTBP1 and the perturbed expression of a PTBP1-target, PKM, are significantly enriched in these patient cells, and associated with the defective oxidative phosphorylation and impaired neurogenesis. Hedgehog-induced oxidative phosphorylation significantly enhances the survival and differentiation capacity of patient cells. In sum, we define various factors associated with Hirschsprung pathogenesis and demonstrate the implications of oxidative phosphorylation in enteric neural crest development and HSCR pathogenesis., (© 2023. The Author(s).)
- Published
- 2023
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