Christelle Cayrou

Cancer is both a genetic and an epigenetic disease, as evidenced by the numerous changes in chromatin structure in tumors. Elevated levels of histone H3 lysine 4 trimethylation (H3K4me3), reflecting transcriptional activation, are associated with poor prognosis in several types of cancer. Although the role of H3K4me3 in transcription has been described in detail, its role in the molecular mechanisms controlling DNA replication remains poorly understood. We recently found that the H3K4me3 mark facilitates heterochromatin replication, supporting the increased proliferation of cancer cells. These observations underline the importance of elucidating the role and molecular mechanisms played by H3K4me3 in the replication of heterochromatin, rich in actively transcribed genes. My project aims to understand how regulation of H3K4me3 localization affects the balance between transcription initiation and DNA replication at replication origins within proximal regulatory regions; how deregulation of H3K4me3 in replication could engage stem cell transformation.  My previous work has revealed the presence of highly conserved replication initiation sites on many regulatory regions (promoter environment) of actively transcribed genes in many organisms. A first exploratory in silico screen in cervical carcinoma (HeLa cells) revealed that several chromatin-associated factors and marks, notably H3K4me3, are highly enriched on these regions. A recent study indicates that temporal deregulation of replication initiation leads to DNA double-strand breaks and chromosomal rearrangements, due to conflicts between replication and transcription. These observations lead us to believe that maintaining the integrity of genetic information requires precise temporal and spatial control of replication initiation in transcription-regulating regions, throughout the cell cycle. We assume that this balance can be maintained by appropriate deposition/suppression of H3K4me3.