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Plasticity of human replication program during differentiation in relation with change in gene expression and chromatin reorganization

Abstract : The sequencing of the human genome, twelve years ago, revealed the complexity of the mechanisms underlying nuclear process such as transcription, replication and chromatin organization. In the past few years, to delineate better these processes, datasets on the cell nucleus were gathered and made available online by numerous laboratories around the world. These datasets are, at once, extraordinarily rich and daunting to handle. In this thesis, we take advantage of these datasets to understand better the nuclear determinants of the replication program. We analyze not less than a hundred ChiP-seq profiles along human chromosomes in several cell lines to characterize the primary structure of chromatin. We demonstrate, when using tools from multivariate statistics, that the immense potential complexity of these datasets can be reduced to four prevalent chromatin states in all studied somatic cell lines. This simple and comprehensive classification is an excellent starting point for the study of replication. The four prevalent chromatin states are replicated at different moments of the S-phase (they have a different replication “timing”) and have drasticaly different gene contents. Their spatial repartition along the genome is structured, especially in domains where the timing replication is U-shaped. These megabase sized U-domains cover 50% of the human genome and the four prevalent chromatin states succeed each other from their borders to their center. The same statistical techniques applied on an embryonic stem cell (ESC) also reduced the epigenetic complexity to four prevalent chromatin states which are qualitatively different from the ones in somatic cells. We further show that the specificities of embryonic replication program are link to the specificities of embryonic chromatin. Importantly, our study reveals that the histone variant H2AZ plays a major role in pluripotency.
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Submitted on : Thursday, February 6, 2014 - 12:03:09 PM
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  • HAL Id : tel-00942719, version 1

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Hanna Julienne. Plasticity of human replication program during differentiation in relation with change in gene expression and chromatin reorganization. Other [cond-mat.other]. Ecole normale supérieure de lyon - ENS LYON, 2013. English. ⟨NNT : 2013ENSL0868⟩. ⟨tel-00942719⟩

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