Gene architecture directs splicing outcome in separate nuclear spatial regions

Luna Tammer, Ofir Hameiri, Ifat Keydar, Vanessa Rachel Roy, Asaf Ashkenazy-Titelman, Noélia Custódio, Itay Sason, Ronna Shayevitch, Victoria Rodríguez-Vaello, José Rino, Galit Lev Maor, Yodfat Leader, Doha Khair, Erez Lieberman Aiden, Ran Elkon, Manuel Irimia, Roded Sharan, Yaron Shav-Tal, Maria Carmo-Fonseca, Gil Ast*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


How the splicing machinery defines exons or introns as the spliced unit has remained a puzzle for 30 years. Here, we demonstrate that peripheral and central regions of the nucleus harbor genes with two distinct exon-intron GC content architectures that differ in the splicing outcome. Genes with low GC content exons, flanked by long introns with lower GC content, are localized in the periphery, and the exons are defined as the spliced unit. Alternative splicing of these genes results in exon skipping. In contrast, the nuclear center contains genes with a high GC content in the exons and short flanking introns. Most splicing of these genes occurs via intron definition, and aberrant splicing leads to intron retention. We demonstrate that the nuclear periphery and center generate different environments for the regulation of alternative splicing and that two sets of splicing factors form discrete regulatory subnetworks for the two gene architectures. Our study connects 3D genome organization and splicing, thus demonstrating that exon and intron definition modes of splicing occur in different nuclear regions.

Original languageEnglish
Pages (from-to)1021-1034.e8
JournalMolecular Cell
Issue number5
StatePublished - 3 Mar 2022


FundersFunder number
Edmond J. Safra Bioinformatics Center
Israel Cancer Research FundICRF PG-18-105
United States - Israel Binational Science FoundationBSF 2017086
German-Israeli Foundation for Scientific Research and DevelopmentGIF I-1460
United States-Israel Binational Science Foundation
Israel Cancer AssociationICA 20170034
Israel Science FoundationISF 2417/20, ISF 671/18, ISF 142/13
Tel Aviv UniversityK562, GM12878
Council for Higher Education


    • 3D genome
    • GC content
    • alternative splicing
    • exon definition
    • exon skipping
    • gene architecture
    • intron definition
    • intron retention
    • nuclear localization
    • splicing factors


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