Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions
CHIBON, Frédéric
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Institut Bergonié [Bordeaux]
Centre de Recherches en Cancérologie de Toulouse [CRCT]
Institut Bergonié [Bordeaux]
ARGOUL, Françoise
Laboratoire Ondes et Matière d'Aquitaine [LOMA]
Laboratoire de Physique de l'ENS Lyon [Phys-ENS]
Laboratoire Ondes et Matière d'Aquitaine [LOMA]
Laboratoire de Physique de l'ENS Lyon [Phys-ENS]
ARNEODO, Alain
Laboratoire Ondes et Matière d'Aquitaine [LOMA]
Laboratoire de Physique de l'ENS Lyon [Phys-ENS]
< Réduire
Laboratoire Ondes et Matière d'Aquitaine [LOMA]
Laboratoire de Physique de l'ENS Lyon [Phys-ENS]
Langue
en
Article de revue
Ce document a été publié dans
Nucleic Acids Research. 2018, vol. 46, n° 19, p. 10157–10172
Oxford University Press
Résumé en anglais
The spatiotemporal program of metazoan DNA repli-cation is regulated during development and altered in cancers. We have generated novel OK-seq, Repli-seq and RNA-seq data to compare the DNA replica-tion and gene expression ...Lire la suite >
The spatiotemporal program of metazoan DNA repli-cation is regulated during development and altered in cancers. We have generated novel OK-seq, Repli-seq and RNA-seq data to compare the DNA replica-tion and gene expression programs of twelve cancer and non-cancer human cell types. Changes in replication fork directionality (RFD) determined by OK-seq are widespread but more frequent within GC-poor isochores and largely disconnected from transcription changes. Cancer cell RFD profiles cluster with non-cancer cells of similar developmental origin but not with different cancer types. Importantly, recurrent RFD changes are detected in specific tumour progression pathways. Using a model for establishment and early progression of chronic myeloid leukemia (CML), we identify 1027 replication initiation zones (IZs) that progressively change efficiency during long-term expression of the BCR-ABL1 onco-gene, being twice more often downregulated than upregulated. Prolonged expression of BCR-ABL1 results in targeting of new IZs and accentuation of previous efficiency changes. Targeted IZs are predominantly located in GC-poor, late replicating gene deserts and frequently silenced in late CML. Prolonged expression of BCR-ABL1 results in massive deletion of GC-poor, late replicating DNA sequences enriched in origin silencing events. We conclude that BCR-ABL1 expression progressively affects replica-tion and stability of GC-poor, late-replicating regions during CML progression.< Réduire
Project ANR
Paris Sciences et Lettres - ANR-10-IDEX-0001
Origine
Importé de halUnités de recherche