A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development
Autor: | Tang, WWC, Dietmann, S, Irie, N, Leitch, HG, Floros, VI, Bradshaw, CR, Hackett, JA, Chinnery, PF, Surani, MA |
---|---|
Přispěvatelé: | Tang, Walfred [0000-0002-5803-1681], Bradshaw, Charles [0000-0002-3528-458X], Hackett, Jamie [0000-0002-6237-3684], Chinnery, Patrick [0000-0002-7065-6617], Surani, Azim [0000-0002-8640-4318], Apollo - University of Cambridge Repository |
Jazyk: | angličtina |
Předmět: |
DYNAMICS
Male Biochemistry & Molecular Biology EPIGENETIC INHERITANCE Retroelements MECHANISMS Epigenesis Genetic Kruppel-Like Factor 4 Mice Animals Humans Gene Regulatory Networks SPECIFICATION Promoter Regions Genetic 11 Medical and Health Sciences Science & Technology Genome Human Biochemistry Genetics and Molecular Biology(all) ERASURE Gene Expression Regulation Developmental Cell Biology IN-VITRO 06 Biological Sciences DNA Methylation Embryo Mammalian TRANSCRIPTION FACTORS Germ Cells Female CELL FATE Life Sciences & Biomedicine Developmental Biology |
Zdroj: | Cell. (6):1453-1467 |
ISSN: | 0092-8674 |
DOI: | 10.1016/j.cell.2015.04.053 |
Popis: | SummaryResetting of the epigenome in human primordial germ cells (hPGCs) is critical for development. We show that the transcriptional program of hPGCs is distinct from that in mice, with co-expression of somatic specifiers and naive pluripotency genes TFCP2L1 and KLF4. This unique gene regulatory network, established by SOX17 and BLIMP1, drives comprehensive germline DNA demethylation by repressing DNA methylation pathways and activating TET-mediated hydroxymethylation. Base-resolution methylome analysis reveals progressive DNA demethylation to basal levels in week 5–7 in vivo hPGCs. Concurrently, hPGCs undergo chromatin reorganization, X reactivation, and imprint erasure. Despite global hypomethylation, evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated. Remarkably, some loci associated with metabolic and neurological disorders are also resistant to DNA demethylation, revealing potential for transgenerational epigenetic inheritance that may have phenotypic consequences. We provide comprehensive insight on early human germline transcriptional network and epigenetic reprogramming that subsequently impacts human development and disease. |
Databáze: | OpenAIRE |
Externí odkaz: |