Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms

Chromosomal translocations have largely been implicated in tumor development. However, beyond the consequences of aberrant gene expression near the breakpoint, their effects remain underexplored. In this work, we characterize the interplay between translocations, chromatin organization and gene expression using mantle cell lymphoma (MCL) as a model. We show by in vitro genomic engineering and in MCL patient samples that translocations can drive transcriptional changes at entire chromosome arms affecting multiple genes in a regulon-like fashion. Moreover, we demonstrate a clear link between the translocation-induced transcriptional alterations and genome organization, with genes most susceptible to change expression forming pre-existing ultra-long-range interactions spanning 50 megabases. The translocation involves the strong immunoglobulin enhancer into this 3D interaction, allowing the spread of its regulatory potential over the entire affected chromosome arm. Finally, we show that translocation-induced effects mainly represent expression enhancement of genes already active prior to translocation formation, highlighting the importance of the epigenetic state of the cell in which this initial hit occurs. In summary, by studying genome organization principles in the context of translocations, we describe a new principle of gene regulation, showing that strong enhancers can induce substantial gene expression enhancement through ultra-long-range interactions affecting entire chromosome arms, representing an important new mechanism in health and disease.

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Publication Details

Journal
Nucleic Acids Research
Published
2025-08-11
DOI
https://doi.org/10.1093/nar/gkaf677
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
0.00

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article

Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms

Alastair Smith, Andrea Rivero, Magda Bienko, Jessica Velten et al.
Nucleic Acids Research
Genomics and Chromatin Dynamics
article

Translocations can drive expression changes of multiple genes in regulons covering entire chromosome arms

Alastair Smith, Andrea Rivero, Magda Bienko, Jessica Velten, Renée Beekman, Kimberly Quililan, Agostina Bianchi, Chloe Gulliver, Luca Cozzuto, Cristina López, A. Marieke Oudelaar, Anna Oncins, Nadia Halidi, Jonas Paulsen, Sı́lvia Beà, Roser Zaurín, François Serra, Johanna Denkena, Leone Albinati, Alfonso Valencia, Erik Wernersson, Raúl Gómez, Magdalena A Karpinska, Houyem Toukabri
article en

Abstract

Chromosomal translocations have largely been implicated in tumor development. However, beyond the consequences of aberrant gene expression near the breakpoint, their effects remain underexplored. In this work, we characterize the interplay between translocations, chromatin organization and gene expression using mantle cell lymphoma (MCL) as a model. We show by in vitro genomic engineering and in MCL patient samples that translocations can drive transcriptional changes at entire chromosome arms affecting multiple genes in a regulon-like fashion. Moreover, we demonstrate a clear link between the translocation-induced transcriptional alterations and genome organization, with genes most susceptible to change expression forming pre-existing ultra-long-range interactions spanning 50 megabases. The translocation involves the strong immunoglobulin enhancer into this 3D interaction, allowing the spread of its regulatory potential over the entire affected chromosome arm. Finally, we show that translocation-induced effects mainly represent expression enhancement of genes already active prior to translocation formation, highlighting the importance of the epigenetic state of the cell in which this initial hit occurs. In summary, by studying genome organization principles in the context of translocations, we describe a new principle of gene regulation, showing that strong enhancers can induce substantial gene expression enhancement through ultra-long-range interactions affecting entire chromosome arms, representing an important new mechanism in health and disease.

Nucleic Acids ResearchVol. 53(15)
Institució Catalana de Recerca i Estudis Avançats (ES), Universitat Pompeu Fabra (ES), University of Oslo (NO), Barcelona Supercomputing Center (ES), Science for Life Laboratory (SE), Parc Científic de la Universitat de València (ES), Karolinska Institutet (SE), Max Planck Institute for Dynamics and Self-Organization (DE), MRC Weatherall Institute of Molecular Medicine (GB), Hospital Clínic de Barcelona (ES), Human Technopole (IT), Centre for Genomic Regulation (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Universitat de Barcelona (ES), University of Göttingen (DE), Universitat Politècnica de Catalunya (ES)
European Molecular Biology Organization, Albert Ellis Institute, Institute for Research in Biomedicine, Centres de Recerca de Catalunya, Generalitat de Catalunya, Vetenskapsrådet, Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación, H2020 European Research Council
Good health and well-being
Openalex Percentile: Top 81%
Genomics and Chromatin Dynamics
DOIOpen Access PDFOpenAlex
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