RNA Fusion in Human Retinal Development

Overview

Journal Elife

Specialty Biology

Date 2024 Jan 2

PMID 38165397

Authors

Wen Wang

Xiao Zhang

Ning Zhao

Ze-Hua Xu

Kangxin Jin

Zi-Bing Jin

Affiliations

Soon will be listed here.

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 () whose downregulation caused precocious neuronal differentiation and a marked reduction of neural progenitors in human cerebral organoids. 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.

References

Hu X, Wang Q, Tang M, Barthel F, Amin S, Yoshihara K . TumorFusions: an integrative resource for cancer-associated transcript fusions. Nucleic Acids Res. 2017; 46(D1):D1144-D1149. PMC: 5753333. DOI: 10.1093/nar/gkx1018. View

Hoon M, Okawa H, Santina L, Wong R . Functional architecture of the retina: development and disease. Prog Retin Eye Res. 2014; 42:44-84. PMC: 4134977. DOI: 10.1016/j.preteyeres.2014.06.003. View

Kim S, Lowe A, Dharmat R, Lee S, Owen L, Wang J . Generation, transcriptome profiling, and functional validation of cone-rich human retinal organoids. Proc Natl Acad Sci U S A. 2019; 116(22):10824-10833. PMC: 6561190. DOI: 10.1073/pnas.1901572116. View

Mootha V, Lindgren C, Eriksson K, Subramanian A, Sihag S, Lehar J . PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003; 34(3):267-73. DOI: 10.1038/ng1180. View

Liu H, Hua Z, Jin Z . Modeling human retinoblastoma using embryonic stem cell-derived retinal organoids. STAR Protoc. 2021; 2(2):100444. PMC: 8058612. DOI: 10.1016/j.xpro.2021.100444. View

Zauhar R, Biber J, Jabri Y, Kim M, Hu J, Kaplan L . As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues. Front Immunol. 2022; 13:895519. PMC: 9240314. DOI: 10.3389/fimmu.2022.895519. View

Tang Y, Qin F, Liu A, Li H . Recurrent fusion RNA DUS4L-BCAP29 in non-cancer human tissues and cells. Oncotarget. 2017; 8(19):31415-31423. PMC: 5458218. DOI: 10.18632/oncotarget.16329. View

Li Y, Wang Y, Wang W, Zhang X, Shen R, Jin K . Second hit impels oncogenesis of retinoblastoma in patient-induced pluripotent stem cell-derived retinal organoids: direct evidence for Knudson's theory. PNAS Nexus. 2023; 1(4):pgac162. PMC: 9802398. DOI: 10.1093/pnasnexus/pgac162. View

Lu Y, Shiau F, Yi W, Lu S, Wu Q, Pearson J . Single-Cell Analysis of Human Retina Identifies Evolutionarily Conserved and Species-Specific Mechanisms Controlling Development. Dev Cell. 2020; 53(4):473-491.e9. PMC: 8015270. DOI: 10.1016/j.devcel.2020.04.009. View

10.

Liu H, Zhang Y, Zhang Y, Li Y, Hua Z, Zhang C . Human embryonic stem cell-derived organoid retinoblastoma reveals a cancerous origin. Proc Natl Acad Sci U S A. 2020; 117(52):33628-33638. PMC: 7776986. DOI: 10.1073/pnas.2011780117. View

11.

Masland R . The neuronal organization of the retina. Neuron. 2012; 76(2):266-80. PMC: 3714606. DOI: 10.1016/j.neuron.2012.10.002. View

12.

Mehani B, Narta K, Paul D, Raj A, Kumar D, Sharma A . Fusion transcripts in normal human cortex increase with age and show distinct genomic features for single cells and tissues. Sci Rep. 2020; 10(1):1368. PMC: 6987184. DOI: 10.1038/s41598-020-58165-6. View

13.

Ma C, Jin K, Jin Z . Generation of Human Patient iPSC-derived Retinal Organoids to Model Retinitis Pigmentosa. J Vis Exp. 2022; (184). DOI: 10.3791/64045. View

14.

Nagase T, Ishikawa K, Suyama M, Kikuno R, Hirosawa M, Miyajima N . Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 1999; 5(6):355-64. DOI: 10.1093/dnares/5.6.355. View

15.

Maruotti J, Sripathi S, Bharti K, Fuller J, Wahlin K, Ranganathan V . Small-molecule-directed, efficient generation of retinal pigment epithelium from human pluripotent stem cells. Proc Natl Acad Sci U S A. 2015; 112(35):10950-5. PMC: 4568212. DOI: 10.1073/pnas.1422818112. View

16.

Ou M, Xiao Q, Ju X, Zeng P, Huang J, Sheng A . The CTNNBIP1-CLSTN1 fusion transcript regulates human neocortical development. Cell Rep. 2021; 35(13):109290. DOI: 10.1016/j.celrep.2021.109290. View

17.

Zhang X, Wang W, Jin Z . Retinal organoids as models for development and diseases. Cell Regen. 2021; 10(1):33. PMC: 8557999. DOI: 10.1186/s13619-021-00097-1. View

18.

Kim H, Cho G, Han S, Shin J, Jeong E, Song S . Novel fusion transcripts in human gastric cancer revealed by transcriptome analysis. Oncogene. 2013; 33(47):5434-41. DOI: 10.1038/onc.2013.490. View

19.

Lidgerwood G, Senabouth A, Smith-Anttila C, Gnanasambandapillai V, Kaczorowski D, Amann-Zalcenstein D . Transcriptomic Profiling of Human Pluripotent Stem Cell-derived Retinal Pigment Epithelium over Time. Genomics Proteomics Bioinformatics. 2020; 19(2):223-242. PMC: 8602392. DOI: 10.1016/j.gpb.2020.08.002. View

20.

Tang Y, Ma S, Wang X, Xing Q, Huang T, Liu H . Identification of chimeric RNAs in human infant brains and their implications in neural differentiation. Int J Biochem Cell Biol. 2019; 111:19-26. DOI: 10.1016/j.biocel.2019.03.012. View