Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions

Xia Wu (1) , Hadi Kabalane (2) , Malik Kahli (1) , Nataliya Petryk (1) , Bastien Laperrousaz (2) , Yan Jaszczyszyn (1) , Guénola Drillon (2) , Frank-Emmanuel Nicolini (3) , Gaëlle Pérot (4) , Aude Robert (5) , Cédric Fund (1, 6) , Frédéric Chibon (7, 8) , Ruohong Xia , Joëlle Wiels (5) , Françoise Argoul (9, 2) , Véronique Maguer-Satta (3) , Alain Arneodo (9, 2) , Benjamin Audit (2) , Olivier Hyrien (1)

1 IBENS - Institut de biologie de l'ENS Paris
2 Phys-ENS - Laboratoire de Physique de l'ENS Lyon
3 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
4 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
5 UMR8126 - Signalisation, noyaux et innovations en cancérologie
6 Genomique ENS - GenomiqueENS
7 CRCT - Centre de Recherches en Cancérologie de Toulouse
8 Institut Bergonié [Bordeaux]
9 LOMA - Laboratoire Ondes et Matière d'Aquitaine

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.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]

Xia Wu, Hadi Kabalane, Malik Kahli, Nataliya Petryk, Bastien Laperrousaz, et al.. Developmental and cancer-associated plasticity of DNA replication preferentially targets GC-poor, lowly expressed and late-replicating regions. Nucleic Acids Research, 2018, 46 (19), pp.10157-10172. ⟨10.1093/nar/gky797⟩. ⟨hal-02363281v2⟩