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A PAX5-OCT4-PRDM1 Developmental Switch Specifies Human Primordial Germ Cells

ABSTRACT: Dysregulation of genetic pathways during germ cell development leads to infertility and tumorigenesis. Here, we used high throughput analyses in bona fide human primordial germ cells (hPGCs) to probe the genetics of human germ cell specification and differentiation and uncover redistribution of OCT4 protein occupancy relative to human embryonic stem cells (hESCs). We demonstrate that the developmental programs from pluripotent stem cell to germ cell formation and differentiation are driven by switching partners with OCT4 protein from SOX2 to PAX5 and PRDM1. Genetic gain- and loss-of-function studies reveal that PAX5 encodes a novel and critical regulator of human germ cell development. Moreover, analysis of epistasis indicates that PAX5 acts upstream, binding to enhancers of OCT4 and PRDM1, to regulate expression during differentiation. The PAX5-OCT4-PRDM1 proteins form a core transcriptional network that activates germline and represses somatic genetic programs. Broadly, these findings also illustrate the power of combined human gene editing, cell differentiation and engraftment for directly probing the genetics of human developmental stages that have historically been difficult to study.

ORGANISM(S): Homo sapiens

PROVIDER: GSE100639 | GEO | 2018/05/16

REPOSITORIES: GEO

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