The Genetic and Epigenetic Basis of Human Genome Replication
DNA replication follows a strict spatiotemporal program with a poorly understood genetic and epigenetic basis. To systematically uncover the genetic components of DNA replication timing regulation, we exploit inter-individual replication timing variation across human cells lines. In this talk, I will mainly describe our analysis of 116 human embryonic stem cell lines. By comparing replication timing variation to genetic polymorphisms, we identified 608 cis-acting replication timing quantitative trait loci (rtQTLs) – base-pair-resolution determinants of DNA replication timing. We show that rtQTLs function individually, or in combinations of proximal and distal regulators, to affect replication initiation activity. We reveal two layers of replication timing control: a histone code for replication initiation, composed of histone H3 trimethylations together with general histone hyperacetylation; and a multi-component layer that combinatorically fine-tunes DNA replication timing. The latter includes active histone marks and pluripotency-related transcription factors that promote early replication, and, conversely, chromosome topology boundary factors that repress replication when bound to DNA. Human replication timing is robustly encoded in DNA sequence and follows principles analogous to transcriptional regulation: a histone code, activators and repressors, and a promoter-enhancer logic.
Domain 2 - UMR 3244 - Dynamics of genetic Information