Fig. 8: Molecular regulation of human germline commitment.

a, Heat map presents gene expression Z-score of the sample set indicated for enriched genes in 4i ES cells (4i), N3⁺PGCLCs (N3), DM⁺PGCLCs (DM), DZ⁺PGCLCs (day (d)4, 4DZ; d8, 8DZ), week 5/7/9 PGCs, migratory, mitotic and mitotic arrest PGCs. piRNA, PIWI-interacting RNA. The data show an integration of two biological replicates. b, Summary scheme for the molecular regulation of human germline commitment. Human PGC specification (approximately weeks 2–3) from the precursors (4i ES cells) in response to BMP2 or BMP4, which induces expression of SOX17 and PRDM1, followed by NANOS3 (N3⁺PGCLCs). Further development occurs by switching the signalling from BMP to Ra and ActA, marked by the expression of CDH5 and DMRT1 (DM⁺PGCLCs), characteristics for migratory/mitotic PGCs (approximately weeks 4–5). Migratory PGCs undergo progressive DNA demethylation through transient 5hmC enrichment, followed by the expression of DAZL (DZ⁺PGCLCs), indicating germline commitment characterized as mitotic arrest status in males (approximately weeks 5–9). Induced expression of SOX17 and PRDM1 can induce NANOS3, but the expression of DMRT1 occurs only in the absence of BMP2, suggesting the suppressive effect on DMRT1. Induced expression of DMRT1 and SOX17 modulates the epigenetic programme, including the enrichment of 5hmC and loss of 5mC directly bound by DMRT1, and the potential regulators, TETs and DNMT3B. DMRT1 is also involved in the suppression of pluripotency genes and induction of later PGC programme, DAZL, PIWIL1 and PIWIL2, as well as specific repeat elements, LTR12C and ALR/Alpha, collectively the hallmarks of germline commitment towards the onset of gametogenesis.