A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development

Summary Resetting 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.

[1]  David Haussler,et al.  An evolutionary arms race between KRAB zinc finger genes 91/93 and SVA/L1 retrotransposons , 2014, Nature.

[2]  Y. Matsui,et al.  Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. , 2005, Developmental biology.

[3]  Frank Lyko,et al.  Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. , 2013, Developmental cell.

[4]  D. Trono,et al.  In Embryonic Stem Cells, ZFP57/KAP1 Recognize a Methylated Hexanucleotide to Affect Chromatin and DNA Methylation of Imprinting Control Regions , 2011, Molecular cell.

[5]  M. Surani,et al.  X Chromosome Activity in Mouse XX Primordial Germ Cells , 2008, PLoS genetics.

[6]  M. Surani,et al.  Epigenetic reprogramming in mouse primordial germ cells , 2002, Mechanisms of Development.

[7]  R. Sachidanandam,et al.  piRNA pathway targets active LINE1 elements to establish the repressive H3K9me3 mark in germ cells , 2014, Genes & development.

[8]  R. Martienssen,et al.  Transgenerational Epigenetic Inheritance: Myths and Mechanisms , 2014, Cell.

[9]  F. Miura,et al.  Amplification-free whole-genome bisulfite sequencing by post-bisulfite adaptor tagging , 2012, Nucleic acids research.

[10]  K. Kurimoto,et al.  Replication‐coupled passive DNA demethylation for the erasure of genome imprints in mice , 2012, The EMBO journal.

[11]  Kun Zhang,et al.  Dynamics of 5-methylcytosine and 5-hydroxymethylcytosine during germ cell reprogramming , 2013, Cell Research.

[12]  Colm E. Nestor,et al.  Promoter DNA methylation couples genome-defence mechanisms to epigenetic reprogramming in the mouse germline , 2012, Development.

[13]  K. Abe,et al.  X Chromosome Reactivation Initiates in Nascent Primordial Germ Cells in Mice , 2007, PLoS genetics.

[14]  M. Azim Surani,et al.  SOX17 Is a Critical Specifier of Human Primordial Germ Cell Fate , 2015, Cell.

[15]  H. Ohta,et al.  Induction of mouse germ-cell fate by transcription factors in vitro , 2013, Nature.

[16]  Peter A. Jones.  Functions of DNA methylation: islands, start sites, gene bodies and beyond , 2012, Nature Reviews Genetics.

[17]  M. Suyama,et al.  Genome-Wide Analysis of DNA Methylation Dynamics during Early Human Development , 2014, PLoS genetics.

[18]  M. Surani,et al.  Primordial germ-cell development and epigenetic reprogramming in mammals. , 2013, Current topics in developmental biology.

[19]  W. Richard McCombie,et al.  Sperm Methylation Profiles Reveal Features of Epigenetic Inheritance and Evolution in Primates , 2011, Cell.

[20]  F. Tang,et al.  The DNA methylation landscape of human early embryos , 2014, Nature.

[21]  J. Nichols,et al.  Resetting Transcription Factor Control Circuitry toward Ground-State Pluripotency in Human , 2014, Cell.

[22]  E. Li,et al.  DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages , 2006, Development.

[23]  W. Reik,et al.  The Dynamics of Genome-wide DNA Methylation Reprogramming in Mouse Primordial Germ Cells , 2012, Molecular cell.

[24]  R. Alberio,et al.  Epigenetic reprogramming in the porcine germ line , 2011, BMC Developmental Biology.

[25]  J. Boeke,et al.  Human Transposon Tectonics , 2012, Cell.

[26]  Aviv Regev,et al.  DNA methylation dynamics of the human preimplantation embryo , 2014, Nature.

[27]  M. Pellegrini,et al.  The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation , 2012, Nature Cell Biology.

[28]  G. Bourque,et al.  The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity , 2014, Nature Structural &Molecular Biology.

[29]  M. Araúzo-Bravo,et al.  Human primordial germ cell commitment in vitro associates with a unique PRDM14 expression profile , 2015, The EMBO journal.

[30]  Antoine H. F. M. Peters,et al.  In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism , 2014, Science.

[31]  E. Bendsen,et al.  Number of germ cells and somatic cells in human fetal ovaries during the first weeks after sex differentiation. , 2006, Human reproduction.

[32]  T. Down,et al.  Germline DNA Demethylation Dynamics and Imprint Erasure Through 5-Hydroxymethylcytosine , 2013, Science.

[33]  E. Diamanti,et al.  A tripartite transcription factor network regulates primordial germ cell specification in mice , 2013, Nature Cell Biology.

[34]  H. Sasaki.  Mechanisms of trophectoderm fate specification in preimplantation mouse development , 2010, Development, growth & differentiation.

[35]  J. Richter,et al.  Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance , 2010, The Journal of pathology.

[36]  Michael Weber,et al.  Global profiling of DNA methylation erasure in mouse primordial germ cells. , 2012, Genome research.

[37]  R. Faria,et al.  A prominent role of KRAB-ZNF transcription factors in mammalian speciation? , 2013, Trends in genetics : TIG.

[38]  Yutaka Suzuki,et al.  High-resolution DNA methylome analysis of primordial germ cells identifies gender-specific reprogramming in mice , 2013, Genome research.

[39]  D. C. Hancks,et al.  Active human retrotransposons: variation and disease. , 2012, Current opinion in genetics & development.