Parent-of-origin-specific DNA replication timing is confined to large imprinted regions
Matthew M. Edwards,
Ning Wang,
Ido Sagi,
Shay Kinreich,
Nissim Benvenisty,
Jeannine Gerhardt,
Dieter Egli,
Amnon Koren
Affiliations
Matthew M. Edwards
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Ning Wang
Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA; Columbia University Stem Cell Initiative, New York, NY 10032, USA
Ido Sagi
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel
Shay Kinreich
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel
Nissim Benvenisty
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University, Jerusalem 91904, Israel; Corresponding author
Jeannine Gerhardt
Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medicine, New York, NY 10065, USA; Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA; Corresponding author
Dieter Egli
Department of Pediatrics and Naomi Berrie Diabetes Center, Columbia University, New York, NY 10032, USA; Columbia University Stem Cell Initiative, New York, NY 10032, USA; Corresponding author
Amnon Koren
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA; Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Corresponding author
Summary: Genomic imprinting involves differential DNA methylation and gene expression between homologous paternal and maternal loci. It remains unclear, however, whether DNA replication also shows parent-of-origin-specific patterns at imprinted or other genomic regions. Here, we investigate genome-wide asynchronous DNA replication utilizing uniparental human embryonic stem cells containing either maternal-only (parthenogenetic) or paternal-only (androgenetic) DNA. Four clusters of imprinted genes exhibited differential replication timing based on parent of origin, while the remainder of the genome, 99.82%, showed no significant replication asynchrony between parental origins. Active alleles in imprinted gene clusters replicated earlier than their inactive counterparts. At the Prader-Willi syndrome locus, replication asynchrony spanned virtually the entirety of S phase. Replication asynchrony was carried through differentiation to neuronal precursor cells in a manner consistent with gene expression. This study establishes asynchronous DNA replication as a hallmark of large imprinted gene clusters.
