Antisense oligonucleotide-mediated perturbation of long non-coding RNA reveals functional features in stem cells and across cell types

Chi Wai Yip; Chung-Chau Hon; Kayoko Yasuzawa; Divya Mundackal Sivaraman; Jordan A. Ramilowski; Youtaro Shibayama; Saumya Agrawal; Anika Vinayak Prabhu; Callum Parr; Jessica Severin; Yan Jun Lan; Josée Dostie; Andreas Petri; Hiromi Nishiyori-Sueki; Michihira Tagami; Masayoshi Itoh; Fernando Martínez López; Tsukasa Kouno; Jen-Chien Chang; Joachim Luginbühl; Masaki Kato; Mitsuyoshi Murata; Wing Hin Yip; Xufeng Shu; Imad Abugessaisa; Akira Hasegawa; Harukazu Suzuki; Sakari Kauppinen; Ken Yagi; Yasushi Okazaki

doi:10.1016/j.celrep.2022.111893

GenomicsCell ReportsDec 1, 2022

Peer-reviewed journal article

Antisense oligonucleotide-mediated perturbation of long non-coding RNA reveals functional features in stem cells and across cell types

Chi Wai Yip iD, Chung-Chau Hon iD, Kayoko Yasuzawa iD, Divya Mundackal Sivaraman iD, Jordan A. Ramilowski iD, Youtaro Shibayama, Saumya Agrawal iD, Anika Vinayak Prabhu iD, Callum Parr iD, Jessica Severin iD, Yan Jun Lan, Josée Dostie iD, Andreas Petri iD, Hiromi Nishiyori-Sueki iD, Michihira Tagami iD, Masayoshi Itoh iD, Fernando Martínez López iD, Tsukasa Kouno, Jen-Chien Chang iD, Joachim Luginbühl, Masaki Kato iD, Mitsuyoshi Murata iD, Wing Hin Yip iD, Xufeng Shu iD, Imad Abugessaisa iD, , Jay W. Shin iD

Abstract

Within the scope of FANTOM6 consortium, we perform a large-scale knockdown of 200 long non-coding RNAs (lncRNAs) in human induced pluripotent stem (iPS) cells, and systematically characterize their roles in self-renewal and pluripotency. We find 36 lncRNAs (18%) exhibiting cell growth inhibition From the knockdown of 123 lncRNAs with transcriptome profiling, 36 lncRNAs (29.3%) show molecular phenotypes. Integrating the molecular phenotypes with chromatin-interaction assays further reveals cis- and trans-interacting partners as potential primary targets. Additionally, cell type enrichment analysis identifies lncRNAs associated with pluripotency while the knockdown of LINC02595, CATG00000090305.1 and RP11-148B6.2 modulates colony formation of iPS cells. We compare our results with previously published fibroblasts phenotyping data and find that 2.9% of the lncRNAs exhibit consistent cell growth phenotype, whereas we observe 58.3% agreement in molecular phenotypes. This highlights molecular phenotyping is more comprehensive in revealing affected pathways.

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