TY - JOUR
T1 - Gene architecture directs splicing outcome in separate nuclear spatial regions
AU - Tammer, Luna
AU - Hameiri, Ofir
AU - Keydar, Ifat
AU - Roy, Vanessa Rachel
AU - Ashkenazy-Titelman, Asaf
AU - Custódio, Noélia
AU - Sason, Itay
AU - Shayevitch, Ronna
AU - Rodríguez-Vaello, Victoria
AU - Rino, José
AU - Lev Maor, Galit
AU - Leader, Yodfat
AU - Khair, Doha
AU - Aiden, Erez Lieberman
AU - Elkon, Ran
AU - Irimia, Manuel
AU - Sharan, Roded
AU - Shav-Tal, Yaron
AU - Carmo-Fonseca, Maria
AU - Ast, Gil
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/3/3
Y1 - 2022/3/3
N2 - 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.
AB - 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.
KW - 3D genome
KW - GC content
KW - alternative splicing
KW - exon definition
KW - exon skipping
KW - gene architecture
KW - intron definition
KW - intron retention
KW - nuclear localization
KW - splicing factors
UR - http://www.scopus.com/inward/record.url?scp=85125233872&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2022.02.001
DO - 10.1016/j.molcel.2022.02.001
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C2 - 35182478
AN - SCOPUS:85125233872
SN - 2052-8426
VL - 82
SP - 1021-1034.e8
JO - Molecular and cellular therapies
JF - Molecular and cellular therapies
IS - 5
ER -