期刊
CELL DEATH & DISEASE
卷 12, 期 7, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-021-03906-2
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资金
- Spanish Ministerio de Ciencia e Innovacion, from the Comunidad de Madrid (MITIC) [SAF2016-75456-R, PID2019-110574RB-I00]
- BBVA Foundation
- [PIE 201920E017]
The truncation of the DIDO gene affects RNA splicing and transcription termination in ESC and MEF, altering gene expression involved in differentiation and reprogramming. DIDO3 interacts with the helicase DHX9, leading to increased nuclear R-loop content and DNA replication stress. These defects result in failure of ESC differentiation and MEF reprogramming.
Embryonic stem cell (ESC) differentiation and somatic cell reprogramming are biological processes governed by antagonistic expression or repression of a largely common set of genes. Accurate regulation of gene expression is thus essential for both processes, and alterations in RNA processing are predicted to negatively affect both. We show that truncation of the DIDO gene alters RNA splicing and transcription termination in ESC and mouse embryo fibroblasts (MEF), which affects genes involved in both differentiation and reprogramming. We combined transcriptomic, protein interaction, and cellular studies to identify the underlying molecular mechanism. We found that DIDO3 interacts with the helicase DHX9, which is involved in R-loop processing and transcription termination, and that DIDO3-exon16 deletion increases nuclear R-loop content and causes DNA replication stress. Overall, these defects result in failure of ESC to differentiate and of MEF to be reprogrammed. MEF immortalization restored impaired reprogramming capacity. We conclude that DIDO3 has essential functions in ESC differentiation and somatic cell reprogramming by supporting accurate RNA metabolism, with its exon16-encoded domain playing the main role.
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