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Génome-wide characterization and comparative analysis of the DNA replication program in 12 human cell lines

Abstract : The spatiotemporal program of DNA replication is regulated during development and altered during cancer progression. We propose an original characterization of the plasticity of the DNA replication program based on the profiling of 12 normal or cancerous human cell lines by the Ok-seq method of purification and sequencing of Okazaki fragments which allows to determine the orientation of the progression of replication forks (RFD) at high resolution (10 kilo bases). Comparative analysis of the RFD profiles shows that the replicative changes allow the classification of the cell lines according to their tissue of origin, the cancerous or non-cancerous nature of the cell line type intervening only in second order. There is no hotspot for the accumulation of replicative changes, they are widely dispersed throughout the genome. Nevertheless, the G+C rich and active gene regions, replicated early in the S phase, have the most stable replication program, they present a high density of efficient replication initiation zones (IZ) conserved between cell lines. In contrast, the late replicated, low gene density and low G+C content regions have few efficient IZs, often specific to a tissue or lineage. This leads us to quantify the degree of dissociation between IZ and activation of transcription. This work provides an original overview of replication program changes during normal or pathological differentiation, including a cell line specific control of IZ in late-replication gene deserts.
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Submitted on : Wednesday, February 12, 2020 - 12:23:57 PM
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  • HAL Id : tel-02475871, version 1

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Hadi Kabalane. Génome-wide characterization and comparative analysis of the DNA replication program in 12 human cell lines. Bioinformatics [q-bio.QM]. Université de Lyon, 2019. English. ⟨NNT : 2019LYSEN063⟩. ⟨tel-02475871⟩

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