Mild expression differences of MECP2 influencing aggressive social behavior

The X-chromosomal MECP2/Mecp2 gene encodes methyl-CpG-binding protein 2, a transcriptional activator and repressor regulating many other genes. We discovered in male FVB/N mice that mild (∼50%) transgenic overexpression of Mecp2 enhances aggression. Surprisingly, when the same transgene was expressed in C57BL/6N mice, transgenics showed reduced aggression and social interaction. This suggests that Mecp2 modulates aggressive social behavior. To test this hypothesis in humans, we performed a phenotype-based genetic association study (PGAS) in >1000 schizophrenic individuals. We found MECP2 SNPs rs2239464 (G/A) and rs2734647 (C/T; 3′UTR) associated with aggression, with the G and C carriers, respectively, being more aggressive. This finding was replicated in an independent schizophrenia cohort. Allele-specific MECP2mRNA expression differs in peripheral blood mononuclear cells by ∼50% (rs2734647: C > T). Notably, the brain-expressed, species-conserved miR-511 binds to MECP2 3′UTR only in T carriers, thereby suppressing gene expression. To conclude, subtle MECP2/Mecp2 expression alterations impact aggression. While the mouse data provides evidence of an interaction between genetic background and mild Mecp2 overexpression, the human data convey means by which genetic variation affects MECP2 expression and behavior

Origin and segregation of the human germline

Acknowledgements This work was supported by the Wellcome Investigator Awards in Science (2094)75/Z/17/Z (to MA Surani), the Wellcome Investigator Awards in Science 096738/Z/11/Z (to MA Surani), the BBSRC research grant G103986 (to MA Surani), the Croucher Postdoctoral Research Fellowship (to WWC Tang), the Wellcome 4-Yr PhD Programme in Stem Cell Biology & Medicine (2038)31/Z/16/Z (to A Castillo-Venzor) and the Cambridge Commonwealth European and International Trust (to A Castillo-Venzor), the Isaac Newton Trust (to WWC Tang), the Butterfield Awards of Great Britain Sasakawa Foundation (to T Kobayashi and MA Surani), and the Astellas Foundation for Research on Metabolic Disorders (to T Kobayashi). The marmoset embryo research is generously supported by the Wellcome Trust (WT RG89228, WT RG9242), the Centre for Trophoblast Research, the Isaac Newton Trust, and JSPS KAKENHI 15H02360, 19H05759. TE Boroviak was supported by a Wellcome Sir Henry Dale Fellowship. JC Marioni acknowledges core support from EMBL and from Cancer Research UK (C9545/A29580), which supports MD Morgan. We would like to thank Roger Barker and Xiaoling He for providing human embryonic tissues and Charles Bradshaw for bioinformatics support. We also thank The Weizmann Institute of Science for the WIS2 human PSC line and the Genomics Core Facility of CRUK Cambridge Institute for sequencing services. We thank members of the Surani laboratory for insightful comments and critical reading of the manuscript.Peer reviewedPublisher PD

Sequential enhancer state remodelling defines human germline competence and specification

Germline-soma segregation is a fundamental event during mammalian embryonic development. Here we establish the epigenetic principles of human primordial germ cell (hPGC) development using in vivo hPGCs and stem cell models recapitulating gastrulation.Wellcome Trust PhD studentship RG86341/PRZI/045 Aracely Castillo-Venzor Wellcome Trust PhD studentship (109146/Z/15/Z) Dawei Su

Tracing the emergence of primordial germ cells from bilaminar disc rabbit embryos and pluripotent stem cells.

Rabbit embryos develop as bilaminar discs at gastrulation as in humans and most other mammals, whereas rodents develop as egg cylinders. Primordial germ cells (PGCs) appear to originate during gastrulation according to many systematic studies on mammalian embryos. Here, we show that rabbit PGC (rbPGC) specification occurs at the posterior epiblast at the onset of gastrulation. Using newly derived rabbit pluripotent stem cells, we show robust and rapid induction of rbPGC-like cells in vitro with WNT and BMP morphogens, which reveals SOX17 as the critical regulator of rbPGC fate as in several non-rodent mammals. We posit that development as a bilaminar disc is a crucial determinant of the PGC regulators, regardless of the highly diverse development of extraembryonic tissues, including the amnion. We propose that investigations on rabbits with short gestation, large litters, and where gastrulation precedes implantation can contribute significantly to advances in early mammalian development

Origin and segregation of the human germline.

Funder: EMBL core supportFunder: Astellas Foundation for Research on Metabolic DisordersFunder: MEXT | Japan Society for the Promotion of ScienceFunder: Cambridge TrustFunder: Croucher FoundationFunder: Great Britain Sasakawa FoundationFunder: Isaac Newton TrustHuman germline-soma segregation occurs during weeks 2-3 in gastrulating embryos. Although direct studies are hindered, here, we investigate the dynamics of human primordial germ cell (PGCs) specification using in vitro models with temporally resolved single-cell transcriptomics and in-depth characterisation using in vivo datasets from human and nonhuman primates, including a 3D marmoset reference atlas. We elucidate the molecular signature for the transient gain of competence for germ cell fate during peri-implantation epiblast development. Furthermore, we show that both the PGCs and amnion arise from transcriptionally similar TFAP2A-positive progenitors at the posterior end of the embryo. Notably, genetic loss of function experiments shows that TFAP2A is crucial for initiating the PGC fate without detectably affecting the amnion and is subsequently replaced by TFAP2C as an essential component of the genetic network for PGC fate. Accordingly, amniotic cells continue to emerge from the progenitors in the posterior epiblast, but importantly, this is also a source of nascent PGCs

Origin and segregation of the human germline.

Human germline-soma segregation occurs during weeks 2-3 in gastrulating embryos. Although direct studies are hindered, here, we investigate the dynamics of human primordial germ cell (PGCs) specification using in vitro models with temporally resolved single-cell transcriptomics and in-depth characterisation using in vivo datasets from human and nonhuman primates, including a 3D marmoset reference atlas. We elucidate the molecular signature for the transient gain of competence for germ cell fate during peri-implantation epiblast development. Furthermore, we show that both the PGCs and amnion arise from transcriptionally similar TFAP2A-positive progenitors at the posterior end of the embryo. Notably, genetic loss of function experiments shows that TFAP2A is crucial for initiating the PGC fate without detectably affecting the amnion and is subsequently replaced by TFAP2C as an essential component of the genetic network for PGC fate. Accordingly, amniotic cells continue to emerge from the progenitors in the posterior epiblast, but importantly, this is also a source of nascent PGCs