Graduate Student Columbia University, United States
Abstract: The mammalian oocyte confers dynamic changes to erase cellular memory and re-establishes the patterns of gene expression, epigenetic modifications of DNA and histones, and of nuclear architecture de novo. Thereby, the oocytes prepares the genome for development of all tissues and cell types in an adult organism. As a crucial element of development is the duplication of the genome. In somatic cells, this duplication occurs through a temporal order termed DNA replication timing. However, the principles of establishment and the regulation of DNA replication timing is not well understood, in particular in human cells. Here we show using single cell whole genome sequencing of human embryos throughout preimplantation development, that a DNA replication timing program is established from the zygote stage, during the period of methylation erasure of DNA and histones. Late replicating regions are positioned in less accessible regions of the genome, characterized by low GC content, sparse replication origins, and an inverse relationship with the active histone marker H3K4me3. Remarkably, these same features determine the pattern of chromosomal fragility under replication stress. This result highlights the basic role of DNA replication timing in shaping genome stability during the earliest stages of mammalian embryo development. Our findings reveal that DNA replication timing is among the earliest layers of epigenetic regulation established after fertilization, acting prior to and potentially upstream of the regulation of gene expression and of most epigenetic modifications.
