Parental haplotype-specific single-cell transcriptomics reveal incomplete epigenetic reprogramming in human female germ cells

• Published in: Nature communications Vol. 9; no. 1; pp. 1873 - 10
• Main Authors: Vértesy, Ábel, Arindrarto, Wibowo, Roost, Matthias S., Reinius, Björn, Torrens-Juaneda, Vanessa, Bialecka, Monika, Moustakas, Ioannis, Ariyurek, Yavuz, Kuijk, Ewart, Mei, Hailiang, Sandberg, Rickard, van Oudenaarden, Alexander, Chuva de Sousa Lopes, Susana M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 38/23; 38/91; 631/136/2086; 631/136/2434/1706; 631/208/176/1968; Abortion, Legal; Adult; Chromosomes; Chromosomes, Human, X - chemistry; Chromosomes, Human, X - metabolism; DNA Methylation; Epigenesis, Genetic; Epigenetics; Exome Sequencing; Female; Fetus; Fetuses; Gene expression; Gene sequencing; Genetic Heterogeneity; Genomes; Genomic Imprinting; Germ cells; Haplotypes; Heterogeneity; Humanities and Social Sciences; Humans; Male; Meiosis; multidisciplinary; Ovum - growth & development; Ovum - metabolism; Pregnancy; Pregnancy Trimesters; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Single-Cell Analysis - methods; Transcription; Transcriptome; X Chromosome Inactivation; X chromosomes; Zebrafish
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04215-7

In contrast to mouse, human female germ cells develop asynchronously. Germ cells transition to meiosis, erase genomic imprints, and reactivate the X chromosome. It is unknown if these events all appear asynchronously, and how they relate to each other. Here we combine exome sequencing of human fetal and maternal tissues with single-cell RNA-sequencing of five donors. We reconstruct full parental haplotypes and quantify changes in parental allele-specific expression, genome-wide. First we distinguish primordial germ cells (PGC), pre-meiotic, and meiotic transcriptional stages. Next we demonstrate that germ cells from various stages monoallelically express imprinted genes and confirm this by methylation patterns. Finally, we show that roughly 30% of the PGCs are still reactivating their inactive X chromosome and that this is related to transcriptional stage rather than fetal age. Altogether, we uncover the complexity and cell-to-cell heterogeneity of transcriptional and epigenetic remodeling in female human germ cells. In mammalian female germ cells, parent-specific epigenetic marks are erased and the X chromosome reactivated before entry into meiosis. Here, by combining parental haplotype reconstruction with single-cell transcriptomics of human female embryonic germ cells, the authors demonstrate that epigenetic reprogramming occurs in a heterogeneous fashion and during a broad time window up to week 14.