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Human germ cell formation in xenotransplants of induced pluripotent stem cells carrying X chromosome aneuploidies

ABSTRACT: Induced pluripotent stem cells (iPSCs) offer opportunity for insight into the genetic requirements of the X chromosome for somatic and germline development. Turner syndrome is caused by complete or partial loss of the second sex chromosome; while more than 90% of Turner cases result in spontaneous fetal loss, survivors display an array of somatic and germline clinical characteristics. Here, we derived iPSCs from Turner syndrome and control individuals and examined germ cell development as a function of X chromosome composition. We analyzed gene expression profiles of derived iPSCs and in vitro differentiated cells by single cell qRT-PCR and RNA-seq. We whoed that two X chromosomes are not necessary for reprogramming or pluripotency maintenance. Genes that escape X chromosome inactivation (XCI) between control iPSCs and those with X chromosome aneuploidies revealed minimal expression differences relative to a female hESC line. Moreover, when we induced germ cell differentiation via murine xenotransplantation of iPSC lines into the seminiferous tubules of busulfan-treated mice, we observed that undifferentiated iPSCs, independent of X chromosome composition, when placed within the correct somatic environment, are capable of forming early germ cells in vivo. Results indicate that two intact X chromosomes are not required for germ cell formation; however, clinical data suggest that two sex chromosomes are required for maintenance of human germ cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55939 | GEO | 2015/05/18

SECONDARY ACCESSION(S): PRJNA241371

REPOSITORIES: GEO

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Human germ cell formation in xenotransplants of induced pluripotent stem cells carrying X chromosome aneuploidies

Project description:Induced pluripotent stem cells (iPSCs) offer opportunity for insight into the genetic requirements of the X chromosome for somatic and germline development. Turner syndrome is caused by complete or partial loss of the second sex chromosome; while more than 90% of Turner cases result in spontaneous fetal loss, survivors display an array of somatic and germline clinical characteristics. Here, we derived iPSCs from Turner syndrome and control individuals and examined germ cell development as a function of X chromosome composition. We analyzed gene expression profiles of derived iPSCs and in vitro differentiated cells by single cell qRT-PCR and RNA-seq. We whoed that two X chromosomes are not necessary for reprogramming or pluripotency maintenance. Genes that escape X chromosome inactivation (XCI) between control iPSCs and those with X chromosome aneuploidies revealed minimal expression differences relative to a female hESC line. Moreover, when we induced germ cell differentiation via murine xenotransplantation of iPSC lines into the seminiferous tubules of busulfan-treated mice, we observed that undifferentiated iPSCs, independent of X chromosome composition, when placed within the correct somatic environment, are capable of forming early germ cells in vivo. Results indicate that two intact X chromosomes are not required for germ cell formation; however, clinical data suggest that two sex chromosomes are required for maintenance of human germ cells. RNA-seq of H9 cells, iPSCs from Turner syndrome and control individuals and in vitro differentiated cells

2015-05-18 | E-GEOD-55939 | biostudies-arrayexpress

Distinct and sexually dimorphic X dosage compensation states in the mammalian germline

Project description:This experiment depicts RNA-Seq datasets from wild type XY male and XX female, as well as sex chromosomally abnormal XO female (Turner syndrome) and XX male (Klinefelter variant syndrome) mouse germ cells before, during and after germline reprogramming. This range from E6.5 epiblasts, fluorescence activated cell sorted (FACS) highly purified populations of germ cells (EGFP-positive) and gonadal somatic cells (EGFP-negative) from both sexes at E9.5, E11.5, E12.5, E14.5, E15.5, E16.5 and E18.5, as well as purified spermatogonia and leptotene / zygotene spermatocytes from P2 and P11 males, respectively. Non-gonadal somatic cell control datasets were generated from male and female E14.5 liver and tail. Germ cells from individual embryos were processed to make cDNA libraries and served as biological replicates. We generated in total 184 libraries for our analysis from 60 separate conditions.

2017-02-06 | E-MTAB-4616 | biostudies-arrayexpress

Scml2 establshes germline-sepcific epigenome

Project description:we identify Scml2, a subunit of a germ cell-specific polycomb repressive complex 1 (PRC1), as a critical epigenetic modifier that establishes the germline-specific epigenome through two distinct functions. One of these functions is in the stem cell phase of spermatogonia and the other is on meiotic sex chromosomes. During the stem cell phase of spermatogonia, Scml2 establishes Rnf2- dependent ubiquitination of H2A (Rnf2-ubH2A) as an epigenetic memory that subsequently ensures programmed repression of somatic genes during the late stages of spermatogenesis. Additionally, during meiosis, Scml2 interacts with M-NM-3H2AX and works downstream of the DNA damage response factor Mdc1 on the sex chromosomes and, contrary to autosomes, suppresses Rnf2-ubH2A for proper epigenetic programming of the sex chromosomes. Taken together, Scml2 positively regulates Rnf2-ubH2A on autosomes and negatively regulates Rnf2-ubH2A on the sex chromosomes to establish the germline-specific epigenome in spermatogenesis. Our study reveals a novel layer of epigenetic regulation in the male germline and adds further insight into the functionality of the polycomb proteins. RNA-seq and ChIP-seq analyses using wild-type and Scml2 KO spermatogenic cells

2015-02-19 | E-GEOD-55060 | biostudies-arrayexpress

Chromosome fusion and programmed DNA elimination shape karyotypes of parasitic nematodes [CUT&RUN]

Project description:A growing list of metazoans undergo programmed DNA elimination (PDE), where a significant amount of DNA is selectively lost from the genome during development. In some nematodes, PDE leads to the removal of the ends of all germline chromosomes. In several species, PDE also eliminates sequences in the interior of the chromosomes, leading to an increased number of somatic chromosomes. The biological significance of these karyotype changes associated with PDE and the origin and evolution of nematode PDE remain largely unknown. Here, we assembled the single pair of germline chromosomes of the horse parasite Parascaris univalens and compared the karyotypes, gene organization within the chromosomes, and PDE features among ascarids. We show that Parascaris converts an XX/XY sex-determination system in the germline into an XX/XO system in the somatic cells. Comparisons of Ascaris, Parascaris, and Baylisascaris chromosomes suggest that PDE existed in the ancestor of these parasites, and their current distinct germline karyotypes were derived from fusion events of the same ancestral smaller chromosomes. PDE resolves these fused germline chromosomes and restores their pre-fusion karyotypes, leading to alterations in genome architecture and gene expression in the somatic cells. Cytological and genomic analyses further reveal the dynamic organization of the Parascaris germline chromosome during meiosis and a potential function for the satellite DNA and the heterochromatin arms. Overall, our results show that chromosome fusion and PDE have been harnessed in these ascarids to shape their karyotypes that could modulate the organization and functions of the genomes.

2024-04-22 | GSE254994 | GEO

Chromosome fusion and programmed DNA elimination shape karyotypes of parasitic nematodes [RNA-seq]

2024-04-22 | GSE254814 | GEO

Chromosome fusion and programmed DNA elimination shape karyotypes of parasitic nematodes [Hi-C]

2024-04-22 | GSE254811 | GEO

SCML2 Establishes the Male Germline Epigenome

Project description:Gametogenesis is dependent on the expression of germline-specific genes. However, it remains unknown how the germline epigenome is distinctly established from that of somatic lineages. Here we show that genes commonly expressed in somatic lineages and spermatogenesis-progenitor cells undergo repression in a genome-wide manner in late stages of the male germline and identify underlying mechanisms. SCML2, a germline-specific subunit of a Polycomb repressive complex 1 (PRC1), establishes the unique epigenome of the male germline through two distinct antithetical mechanisms. SCML2 works with PRC1 and promotes RNF2-dependent ubiquitination of H2A, thereby marking somatic/progenitor genes on autosomes for repression. Paradoxically, SCML2 also prevents RNF2-dependent ubiquitination of H2A on sex chromosomes during meiosis, thereby enabling unique epigenetic programming of sex chromosomes for male reproduction. Our results reveal divergent mechanisms involving a shared regulator by which the male germline epigenome is distinguished from that of the soma and progenitor cells.

2015-02-19 | GSE55060 | GEO

Global analysis of X chromosome dosage compensation

Project description:We have conducted a global analysis of somatic dosage compensation and also asked if germ cell dosage compensate by microarray analysis of gene expression in wild-type tissues. To obviate the confounding effects of scatter and especially the skewed genomic distributions of genes with sex-biased expression in both the soma and germline [there are fewer X chromosome genes with male-biased expression], we used mutations that transform sexual identity. In the soma we used gain-of-function transformer to turn X;AA flies into somatic females with tumorous germlines. The gonadectomized somas of these X;AA female flies were compared to similarly prepared XX;AA females. The X;AA ovarian tumors, which are possibly the result of germline sex transformations, were compared to the similar XX;AA ovarian tumors generated with loss-of-function alleles of ovarian tumor and Sex-lethal. We used alleles of transformer-2 and doublesex to transform XX;AA flies into somatic males with atrophic germlines. Keywords: other

2005-12-15 | GSE2119 | GEO

Amniotic fluid RNA gene expression profiling provides insights into the phenotype of Turner syndrome

Project description:Background: Turner syndrome, a common sex chromosome aneuploidy, has characteristics and malformations associated with the phenotype. Fetal amniotic fluid is a complex biological material that could contribute to the understanding Turner syndrome pathogenesis. Global gene expression analysis of Turner syndrome fetal amniotic fluid supernatant was utilized to identify organ systems and specific genes that may play a role in the pathophysiologic changes that are seen in individuals with Turner syndrome. Methods: Global gene expression analysis was performed utilizing cell-free RNA from five midtrimester fetuses with Turner syndrome matched with five euploid female fetuses. Total RNA was extracted, amplified, hybridized onto GeneChip® Human Genome U133 Plus 2.0 arrays. Network and pathway analysis of differentially expressed genes were completed. Chromosomal distribution of gene expression differences, differential expression by pathway and organ system (a “Turner syndrome core transcriptome”), and candidate genes that could play a pathological role were identified. Results: There were 470 differentially expressed genes identified in the Turner syndrome transcriptome. The differentially expressed genes were distributed randomly across different chromosomes. Among genes on the X chromosome, XIST was down-regulated, and SHOX not differentially expressed. The most highly represented organ systems were hematologic/immune and neurologic. Increased representation of differentially expressed genes in the hematologic/immune system distinguishes the Turner syndrome transcriptome from the euploid, trisomy 18 and trisomy 21 transcriptomes previously studied in our laboratory. Manual curation of the differentially expressed gene list identified genes including NFATC3, IGFBP5, and LDLR that warrant further study.

2014-06-13 | GSE58435 | GEO

Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification

Project description:We report the identification of 67 previously undescribed histone modifications, increasing the current number of known histone marks by about 70%. We further investigated one of the marks, lysine crotonylation (Kcr), confirming that it represents an evolutionarily-conserved histone posttranslational modification. The unique structure and genomic localization of histone Kcr suggest that it is mechanistically and functionally different from histone lysine acetylation (Kac). Specifically, in both human somatic and mouse male germ cell genomes, histone Kcr marks either active promoters or potential enhancers. In male germinal cells immediately following meiosis, Kcr is enriched on sex chromosomes and specifically marks testis-specific genes, including a significant proportion of X-linked genes that escape sex chromosome inactivation in haploid cells. These results therefore dramatically extend the repertoire of histone PTM sites and designate Kcr as a specific mark of active sex chromosome-linked genes in postmeiotic male germ cells.

2011-10-06 | GSE32663 | GEO

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