P-276 Telomeres cooperate in zygotic genome activation by affecting DUX4/Dux transcription

Abstract

Abstract Study question Whether the activation of DUX4, a key inducer in the process of zygotic genome activation (ZGA), is associated with telomere length. Summary answer Telomeres regulate the expression of DUX4/Dux through chromatin remodeling and are thereby involved in ZGA. What is known already In human early embryos, the expression of DUX4 is activated as a key inducer in the initial stage of ZGA, and it, in turn, activates hundreds of genes in the cleavage-stage embryo. Human DUX4 is localized to the subtelomeric region 4q35.2 with a D4Z4 repeat of approximately 10 to 100 units that encodes a homeodomain transcription factor. DUX4 expression is inversely proportional to the telomere length in myoblasts/myotubes derived from FSHD patients Study design, size, duration We characterize the dynamics of telomeres during preimplantation development, and assessed the relationship between the expression of DUX4/Dux and telomere length in preimplantation embryos and human embryonic stem cells. Participants/materials, setting, methods All sperm and immature oocytes were collected after obtaining written informed consent from the donor couples. Telomere length in gametes and early embryos by telomere-specific quantitative fluorescence in situ hybridization (Q-FISH). Main results and the role of chance Zygotic genome activation (ZGA) is initiated once the genome chromatin state is organized in the newly formed zygote. While telomeres are specialized chromatin structures at the ends of chromosomes and are reset during early embryogenesis, the details and significance of telomere changes in preimplantation embryos remain unclear. We demonstrated that the telomere length was shortened in the minor ZGA stage and significantly elongated in the major ZGA stage of human and mouse embryos. Expression of the ZGA pioneer factor DUX4/Dux was negatively correlated with the telomere length. ATAC-sequencing suggested that the chromatin accessibility peaks on the DUX4 promoter region (i.e., the subtelomere of chromosome 4q) were transiently augmented in human minor ZGA. Reduction of telomeric heterochromatin H3K9me3 in the telomeric region also synergistically activated DUX4 expression with p53 in hESCs. We propose herein that telomeres regulate the expression of DUX4/Dux through chromatin remodeling and are thereby involved in ZGA. Limitations, reasons for caution Since the mouse Dux gene is not located at the end of the chromosome, the classical telomere position effect (TPE) pathway may not involve in its activation in early embryos. 3D analysis as presented by Hi-C may be able to make a greater breakthrough in confirming the relationship. Wider implications of the findings We herein provided detailed data on changes in the telomere length during ZGA in human and mouse preimplantation embryos, explored the possibility that the TPE affects regulation of DUX4/Dux gene expression in embryos, and suggest that telomere chromatin remodeling is involved in the ZGA process. Trial registration number not applicable