RNA Fusion in human retinal development

  1. Wen Wang
  2. Xiao Zhang
  3. Ning Zhao
  4. Ze-Hua Xu
  5. Kangxin Jin  Is a corresponding author
  6. Zi-Bing Jin  Is a corresponding author
  1. Capital Medical University, China
  2. Beijing Institute of Ophthalmology, 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 (CNS) 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 (hESC)-derived retinal organoids (ROs) spanning from day 0 to day 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, retinal organoids and cell lines; however, its loss-of-function biased the progenitor cells toward retinal pigment epithelial (RPE) 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.

Data availability

Sequencing data have been deposited in GSA under accession codes PRJCA020237.All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 4C and 5AB.

The following previously published data sets were used

Article and author information

Author details

  1. Wen Wang

    Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiao Zhang

    Beijing Institute of Ophthalmology, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Ning Zhao

    Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Ze-Hua Xu

    Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Kangxin Jin

    Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China
    For correspondence
    jinkx@mail.ccmu.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0108-6948
  6. Zi-Bing Jin

    Beijing Institute of Ophthalmology, Capital Medical University, Beijing, China
    For correspondence
    jinzibing@foxmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0515-698X

Funding

National Natural Science Foundation of China (82125007)

  • Zi-Bing Jin

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: One human retinal sample was included in this study, which was derived from a patient's donation. The study was approved by the Ethics Committee of Beijing Tongren Hospital (NO.TRECKY2021-089) and conducted in accordance with the Declaration of Helsinki.

Reviewing Editor

  1. Rebecca M Sappington, Wake Forest Baptist Medical Center, United States

Version history

  1. Preprint posted: November 10, 2022 (view preprint)
  2. Received: September 5, 2023
  3. Accepted: December 14, 2023
  4. Accepted Manuscript published: January 2, 2024 (version 1)
  5. Accepted Manuscript updated: January 3, 2024 (version 2)

Copyright

© 2024, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 425
    Page views
  • 150
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Wen Wang
  2. Xiao Zhang
  3. Ning Zhao
  4. Ze-Hua Xu
  5. Kangxin Jin
  6. Zi-Bing Jin
(2024)
RNA Fusion in human retinal development
eLife 13:e92523.
https://doi.org/10.7554/eLife.92523

Share this article

https://doi.org/10.7554/eLife.92523

Further reading

    1. Developmental Biology
    2. Evolutionary Biology
    Paul Knabl, Alexandra Schauer ... Grigory Genikhovich
    Research Article

    BMP signaling has a conserved function in patterning the dorsal-ventral body axis in Bilateria and the directive axis in anthozoan cnidarians. So far, cnidarian studies have focused on the role of different BMP signaling network components in regulating pSMAD1/5 gradient formation. Much less is known about the target genes downstream of BMP signaling. To address this, we generated a genome-wide list of direct pSMAD1/5 target genes in the anthozoan Nematostella vectensis, several of which were conserved in Drosophila and Xenopus. Our ChIP-seq analysis revealed that many of the regulatory molecules with documented bilaterally symmetric expression in Nematostella are directly controlled by BMP signaling. We identified several so far uncharacterized BMP-dependent transcription factors and signaling molecules, whose bilaterally symmetric expression may be indicative of their involvement in secondary axis patterning. One of these molecules is zswim4-6, which encodes a novel nuclear protein that can modulate the pSMAD1/5 gradient and potentially promote BMP-dependent gene repression.

    1. Biochemistry and Chemical Biology
    2. Developmental Biology
    Sima Stroganov ,  Talia   Harris  ... Michal Neeman
    Research Article

    Background: Fetal growth restriction (FGR) is a pregnancy complication in which a newborn fails to achieve its growth potential, increasing the risk of perinatal morbidity and mortality. Chronic maternal gestational hypoxia, as well as placental insufficiency are associated with increased FGR incidence; however, the molecular mechanisms underlying FGR remain unknown.

    Methods: Pregnant mice were subjected to acute or chronic hypoxia (12.5% O2) resulting in reduced fetal weight. Placenta oxygen transport was assessed by blood oxygenation level dependent (BOLD) contrast magnetic resonance imaging (MRI). The placentae were analyzed via immunohistochemistry and in situ hybridization. Human placentae were selected from FGR and matched controls and analyzed by immunohistochemistry (IHC). Maternal and cord sera were analyzed by mass spectrometry.

    Results: We show that murine acute and chronic gestational hypoxia recapitulates FGR phenotype and affects placental structure and morphology. Gestational hypoxia decreased labyrinth area, increased the incidence of red blood cells (RBCs) in the labyrinth while expanding the placental spiral arteries (SpA) diameter. Hypoxic placentae exhibited higher hemoglobin-oxygen affinity compared to the control. Placental abundance of Bisphosphoglycerate mutase (BPGM) was upregulated in the syncytiotrophoblast and spiral artery trophoblast cells (SpA TGCs) in the murine gestational hypoxia groups compared to the control. Hif1a levels were higher in the acute hypoxia group compared to the control. In contrast, human FGR placentae exhibited reduced BPGM levels in the syncytiotrophoblast layer compared to placentae from healthy uncomplicated pregnancies. Levels of 2,3 BPG, the product of BPGM, were lower in cord serum of human FGR placentae compared to control. Polar expression of BPGM, was found in both human and mouse placentae syncytiotrophoblast, with higher expression facing the maternal circulation. Moreover, in the murine SpA TGCs expression of BPGM was concentrated exclusively in the apical cell side, in direct proximity to the maternal circulation.

    Conclusions: This study suggests a possible involvement of placental BPGM in maternal-fetal oxygen transfer, and in the pathophysiology of FGR.

    Funding: This work was supported by the Weizmann Krenter Foundation and the Weizmann - Ichilov (Tel Aviv Sourasky Medical Center) Collaborative Grant in Biomedical Research, and by the Minerva Foundation (to MN), by the ISF KillCorona grant 3777/19 (to MN, MK).