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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

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

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.

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

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

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Role of LARP7 in meiotic sex chromosome silencing

Project description:Meiotic sex chromosome inactivation (MSCI) is an essential event in meiotic progression in mammalian spermatogenesis. We found that La Ribonucleoprotein 7 (LARP7) is involved in MSCI. LARP7 plays a role in fetal germ cells to promote their proliferation, but is once abolished in postnatal gonocytes and re-expresses in spermatocytes at the onset of meiosis. In spermatocytes, LARP7 localizes to the XY body, a compartmentalized chromatin domain on sex chromosomes. This study aimed to elucidate a possible function of LARP7 in the XY body by using germline-specific Larp7-deficient mice.

2024-10-01 | GSE261526 | 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

A conserved germline-specific Dsn1 alternative splice isoform supports oocyte and embryo development

Project description:Alternative RNA splicing can generate distinct protein isoforms to allow for the differential control of cell processes across cell types. The chromosome segregation and cell division programs associated with somatic mitosis and germline meiosis display dramatic differences such as kinetochore orientation, cohesin removal, or the presence of a gap phase. These changes in chromosome segregation require alterations to the established cell division machinery. However, it remains unclear what aspects of kinetochore function and its regulatory control differ between the mitotic and meiotic cell divisions to rewire these core processes. Additionally, the alternative splice isoforms that differentially modulate distinct cell division programs have remained elusive. Here, we demonstrate that mammalian germ cells express an alternative mRNA splice isoform for the kinetochore component, DSN1, a subunit of the MIS12 complex that links the centromeres to spindle microtubules during chromosome segregation. This germline DSN1 isoform bypasses the requirement for Aurora kinase phosphorylation for its centromere localization due to the absence of a key regulatory region allowing DSN1 to display persistent centromere localization. Expression of the germline DSN1 isoform in somatic cells results in constitutive kinetochore localization, chromosome segregation errors, and growth defects, providing an explanation for its tight cell type-specific expression. Reciprocally, precisely eliminating expression of the germline-specific DSN1 splice isoform in mouse models disrupts oocyte maturation and early embryonic divisions coupled with a reduction in fertility. Together, this work identifies a germline-specific splice isoform for a chromosome segregation component and implicates its role in mammalian fertility.

2024-08-28 | PXD054119 | Pride

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

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