Single-cell multi-omic analysis profiles defective genome activation and epigenetic reprogramming associated with human pre-implantation embryo arrest
Jose Ramon Hernandez Mora,
Claudia Buhigas,
Stephen Clark,
Raquel Del Gallego Bonilla,
Dagne Daskeviciute,
Ana Monteagudo-Sánchez,
Maria Eugenia Poo-Llanillo,
Jose Vicente Medrano,
Carlos Simón,
Marcos Meseguer,
Gavin Kelsey,
David Monk
Affiliations
Jose Ramon Hernandez Mora
Bellvitge Institute for Biomedical Research, 08908 Barcelona, Spain
Claudia Buhigas
Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7JT, UK
Stephen Clark
The Babraham Institute, Babraham, Cambridge CB22 3AT, UK
Raquel Del Gallego Bonilla
IVI-RMA Global and Health Research Institute la Fe, 46026 Valencia, Spain
Dagne Daskeviciute
Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7JT, UK
Ana Monteagudo-Sánchez
Bellvitge Institute for Biomedical Research, 08908 Barcelona, Spain
Maria Eugenia Poo-Llanillo
Igenomix SL, 46980 Valencia, Spain
Jose Vicente Medrano
IVI-RMA Global and Health Research Institute la Fe, 46026 Valencia, Spain; Department of Obstetrics and Gynecology, Valencia University and INCLIVA, 46010 Valencia, Spain
Carlos Simón
Department of Obstetrics and Gynecology, Valencia University and INCLIVA, 46010 Valencia, Spain; Department of Obstetrics and Gynecology, BIDMC, Harvard University, Boston, MA 02215, USA
Marcos Meseguer
IVI-RMA Global and Health Research Institute la Fe, 46026 Valencia, Spain
Gavin Kelsey
The Babraham Institute, Babraham, Cambridge CB22 3AT, UK; Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EL, UK; Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, Cambridge CB2 0QQ, UK
David Monk
Bellvitge Institute for Biomedical Research, 08908 Barcelona, Spain; Biomedical Research Centre, School of Biological Sciences, University of East Anglia, Norwich Research Park, Norwich NR4 7JT, UK; Corresponding author
Summary: During pre-implantation stages of mammalian development, maternally stored material promotes both the erasure of the sperm and oocyte epigenetic profiles and is responsible for concomitant genome activation. Here, we have utilized single-cell methylome and transcriptome sequencing (scM&T-seq) to quantify both mRNA expression and DNA methylation in oocytes and a developmental series of human embryos at single-cell resolution. We fully characterize embryonic genome activation and maternal transcript degradation and map key epigenetic reprogramming events in developmentally high-quality embryos. By comparing these signatures with early embryos that have undergone spontaneous cleavage-stage arrest, as determined by time-lapse imaging, we identify embryos that fail to appropriately activate their genomes or undergo epigenetic reprogramming. Our results indicate that a failure to successfully accomplish these essential milestones impedes the developmental potential of pre-implantation embryos and is likely to have important implications, similar to aneuploidy, for the success of assisted reproductive cycles.
