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RNA fusion in human retinal development
Wen Wang1, Xiao Zhang1, Ning Zhao1
1Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Abstract:
Chimeric RNAs have been found in both cancerous and healthy human cells. They have regulatory effects on human stem/progenitor cell differentiation, stemness maintenance, and central nervous system development. However, whether they are present in human retinal cells and their physiological functions in the retinal development remain unknown. Based on the human embryonic stem cell-derived retinal organoids (ROs) spanning from days 0 to 120, we present the expression atlas of chimeric RNAs throughout the developing ROs. We confirmed the existence of some common chimeric RNAs and also discovered many novel chimeric RNAs during retinal development. We focused on CTNNBIP1-CLSTN1 (CTCL) whose downregulation caused precocious neuronal differentiation and a marked reduction of neural progenitors in human cerebral organoids. CTCL is universally present in human retinas, ROs, and retinal cell lines, and its loss-of-function biases the progenitor cells toward retinal pigment epithelial cell fate at the expense of retinal cells. Together, this work provides a landscape of chimeric RNAs and reveals evidence for their critical role in human retinal development.
Insights
Chimeric RNAs are present in human retinal cells and influence retinal development. Their downregulation disrupts retinal cell differentiation, impacting eye development.
Area of Science:
- Genetics
- Developmental Biology
- Ophthalmology
Background:
- Chimeric RNAs are found in human cells and regulate stem cell functions and neural development.
- Their presence and role in human retinal development are currently unknown.
Purpose of the Study:
- To investigate the expression atlas of chimeric RNAs during human retinal development.
- To determine the physiological functions of chimeric RNAs in the developing human retina.
Main Methods:
- Utilized human embryonic stem cell-derived retinal organoids (ROs) from day 0 to 120.
- Analyzed chimeric RNA expression patterns and performed loss-of-function studies on a specific chimeric RNA (CTCL).
Main Results:
- Identified common and novel chimeric RNAs during retinal development.
- Confirmed universal presence of CTNNBIP1-CLSTN1 (CTCL) chimeric RNA in human retinas and retinal organoids.
- Demonstrated that CTCL downregulation leads to precocious neuronal differentiation and a shift in progenitor cell fate towards retinal pigment epithelium at the expense of retinal cells.
Conclusions:
- Chimeric RNAs play a critical role in human retinal development.
- CTCL is essential for proper retinal cell differentiation and fate determination.
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