Journal Article

The genetic architecture of DNA replication timing in human pluripotent stem cells

Hsiao, Joyce, Eggan, Kevin, Charvet, Christine J., Ghosh, Sulagna, Wang, Ning, Bracci, Alexa N., Koren, Amnon, Clark, Andrew G., Hulke, Michelle L., Hu, Ya, Merkle, Florian T., Zhu, Xiang, Handsaker, Robert E., Edwards, Matthew M., Gerhardt, Jeannine, Egli, Dieter, Tong, Yao, Ding, Qiliang

2021

Overview

DNA replication follows a strict spatiotemporal program that intersects with chromatin structure but has a poorly understood genetic basis. To systematically identify genetic regulators of replication timing, we exploited inter-individual variation in human pluripotent stem cells from 349 individuals. We show that the human genome’s replication program is broadly encoded in DNA and identify 1,617 cis -acting replication timing quantitative trait loci (rtQTLs) – sequence determinants of replication initiation. rtQTLs function individually, or in combinations of proximal and distal regulators, and are enriched at sites of histone H3 trimethylation of lysines 4, 9, and 36 together with histone hyperacetylation. H3 trimethylation marks are individually repressive yet synergistically associate with early replication. We identify pluripotency-related transcription factors and boundary elements as positive and negative regulators of replication timing, respectively. Taken together, human replication timing is controlled by a multi-layered mechanism with dozens of effectors working combinatorially and following principles analogous to transcription regulation. The genetic basis of how cells replicate their DNA is not well understood. Here, the authors identify >1000 genetic elements that control human replication and reveal a complex epigenetic system that regulates replication origin activities.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/100 / 45/23 / 45/43 / 631/208/457 / 631/208/726 / 631/337/151 / 631/337/176 / Acetylation / Biological Variation, Population - genetics / Chromatin / Datasets as Topic / Deoxyribonucleic acid / DNA / DNA biosynthesis / DNA Methylation / DNA Replication Timing / Epigenetics / Female / Gene Expression Regulation / Gene mapping / Gene regulation / Genome, Human / Genomes / Histone Code - genetics / Histone H3 / Histones / Histones - metabolism / Humanities and Social Sciences / Humans / Male / multidisciplinary / Multilayers / Pluripotency / Pluripotent Stem Cells - metabolism / Quantitative Trait Loci / Replication / Replication initiation / Replication origins / Science / Science (multidisciplinary) / Stem cells / Transcription factors / Transcription Factors - metabolism / Whole Genome Sequencing