Ontology highlight
ABSTRACT:
PROVIDER: PRJEB28344 | ENA |
REPOSITORIES: ENA
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Project description:In our study, scWES was employed on oocytes from female mice with different reproductive ages. We also performed whole exome sequencing on bluk blood samples in trios to detect de novo germline variations in oocytes. Both natural aging and accelerated reproductive aging were involved. We demonstrated that genetic alterations, including base variants and structural variations, occurred in mouse oocytes during aging. Genes harboring natural aging or accelerated aging-related de novo germline variants (DNGVs) were almost involved in Ugt1a, V2R, and Mucin gene families. A copy number variant (CNV) associated with chromatin modeling were detected in natural aging oocytes. More importantly, we shortlisted various critical biological functions, like calcium binding pathway and p53 pathways, affected by these aging-related genetic alterations. Our work is the first study to identify genetic alterations in mouse oocytes with in vivo aging and offers a new direction of dissecting the aging mechanisms in oocytes and clarifying genetic causes of lower fertility at advanced maternal age.
2019-08-01 | PRJEB28344 | EVA
Project description:Background: Severe combined immunodeficiency (SCID) is characterized by arrested T lymphocyte production and B lymphocyte dysfunction, resulting in life-threatening infections. Early diagnosis of SCID through population-based newborn screening (NBS) optimizes clinical management and outcomes, and also permits identification of previously unknown factors essential for human lymphocyte development. Methods: SCID was detected, prior to onset of infections, by NBS of T cell receptor excision circles, a biomarker for thymic output. Upon confirmation, the affected baby was treated by allogeneic hematopoietic cell transplantation (HCT). The genetic cause was sought by exome sequencing of the patient and parents, followed by functional analysis of a prioritized candidate gene using human hematopoietic stem cells (HSC) and zebrafish embryos. Results: An infant with leaky SCID, craniofacial and dermal abnormalities, and absent corpus callosum had his immune deficit fully corrected by HCT. Exome sequencing revealed a heterozygous, de novo, missense mutation pN441K in BCL11B. The mutant Bcl11b protein had dominant negative activity, abrogating the ability of wild type Bcl11b to bind DNA, arresting T cell lineage development and disrupting HSC migration, revealing a novel function of Bcl11b. The patientâs defects, recapitulated in Bcl11b-deficient zebrafish, were reversed by ectopic expression of intact, but not mutant, human BCL11B. Conclusions: Newborn screening facilitated treatment and identification of a novel etiology for human SCID. Coupling exome sequencing with candidate gene evaluation in human HSC and in zebrafish revealed that a constitutional BCL11B mutation causes human multisystem anomalies with SCID, while also revealing a novel, pre-thymic role for Bcl11b in hematopoietic progenitors. 3 samples were analyzed in duplicate, Sample 1 was human HSC transduced with GFP only lentivirus which served as controls, Sample 2 was human HSC transduced with lentivirus expressing FLAG-tagged WT BCL11B and GFP, Sample 3 was human HSC transduced with lentivirus expressing FLAG-tagged mutant BCL11B and GFP
2016-07-29 | E-GEOD-84941 | biostudies-arrayexpress
Project description:While de novo DNA methylation (DNAme) in mammalian germ cells is dependent upon DNMT3A and DNMT3L, oocytes and spermatozoa show distinct patterns of DNAme. In mouse oocytes, de novo DNAme requires the lysine methyltransferase (KMTase) SETD2, which deposits H3K36me3. Surprisingly, we show here that SETD2 is dispensable for de novo DNAme in the male germline. Rather, the KMTase NSD1, which broadly deposits H3K36me2 in euchromatic regions, plays a critical role in de novo DNAme in prospermatogonia, including of imprinted genes. However, males deficient in germline NSD1 show a more severe defect in spermatogenesis than Dnmt3l-/- males. Furthermore, unlike DNMT3L, NSD1 safeguards a subset of genes against H3K27me3-associated transcriptional silencing. In contrast, H3K36me2 plays only a minor role in de novo DNAme during oogenesis and females with NSD1 deficient oocytes are fertile. Thus, the sexually dimorphic pattern of DNAme in mature mouse gametes is driven by distinct profiles of H3K36 methylation.
2020-07-10 | GSE148150 | GEO
Project description:The integrity of chromatin, which provides a dynamic template for all DNA-related processes in eukaryotes, is maintained through replication-dependent and -independent assembly pathways. To address the role of replication-independent histone deposition, we deleted the histone H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is highly dynamic, and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and, ultimately, a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. In contrast to the only minor transcriptional phenotype observed in mouse pluripotent cells, we unequivocally show the importance of histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in an in vivo context. RNA-Seq on 4 Hiraf/f and 4 Hiraf/f, Zp3-Cre single MII oocytes.
2015-11-03 | E-GEOD-73381 | biostudies-arrayexpress
Project description:The integrity of chromatin, which provides a dynamic template for all DNA related processes in eukaryotes, is maintained through replication dependent and independent assembly pathways. To address the role of replication independent histone deposition, we deleted the histone H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is highly dynamic, and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and, ultimately, a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. In contrast to the only minor transcriptional phenotype observed in mouse pluripotent cells, we unequivocally show the importance of histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in an in vivo context. RNA-Seq on 4 Hiraf/f and 4 Hiraf/f, Gdf9-Cre+ single MII oocytes
2015-11-03 | E-GEOD-66931 | biostudies-arrayexpress
Project description:We have identified de novo copy number variations (CNVs) generated in ageing bulls. Blood samples from eight bulls were collected and SNP arrayed in a prospective design over 30 months allowing us to differentiate de novo CNVs from constant CNVs that are present throughout the sampling period. Quite remarkably, the total number of CNVs doubled over the 30-month period, as we observed an almost equal number of de novo and constant CNVs (107 vs. 111 or 49% vs. 51%, respectively). Twice as many de novo CNVs emerged during the second half of the sampling schedule as in the first part. It suggests a dynamic generation of de novo CNVs in the bovine genome that becomes more frequent, as the age of the animal progresses. In a second experiment de novo CNVs were detected through in vitro ageing of bovine fibroblasts by sampling passage #5, #15 and #25. De novo CNVs also became more frequent, but the proportion of them was only ~25% of the total number of CNVs (21 vs. 64). Temporal generation of de novo CNVs resulted in increasing genome coverage. Genes and quantitative trait loci overlapping de novo CNVs were further investigated for ageing related functions.
2017-03-03 | GSE95612 | GEO
Project description:Background: Severe combined immunodeficiency (SCID) is characterized by arrested T lymphocyte production and B lymphocyte dysfunction, resulting in life-threatening infections. Early diagnosis of SCID through population-based newborn screening (NBS) optimizes clinical management and outcomes, and also permits identification of previously unknown factors essential for human lymphocyte development. Methods: SCID was detected, prior to onset of infections, by NBS of T cell receptor excision circles, a biomarker for thymic output. Upon confirmation, the affected baby was treated by allogeneic hematopoietic cell transplantation (HCT). The genetic cause was sought by exome sequencing of the patient and parents, followed by functional analysis of a prioritized candidate gene using human hematopoietic stem cells (HSC) and zebrafish embryos. Results: An infant with leaky SCID, craniofacial and dermal abnormalities, and absent corpus callosum had his immune deficit fully corrected by HCT. Exome sequencing revealed a heterozygous, de novo, missense mutation pN441K in BCL11B. The mutant Bcl11b protein had dominant negative activity, abrogating the ability of wild type Bcl11b to bind DNA, arresting T cell lineage development and disrupting HSC migration, revealing a novel function of Bcl11b. The patient’s defects, recapitulated in Bcl11b-deficient zebrafish, were reversed by ectopic expression of intact, but not mutant, human BCL11B. Conclusions: Newborn screening facilitated treatment and identification of a novel etiology for human SCID. Coupling exome sequencing with candidate gene evaluation in human HSC and in zebrafish revealed that a constitutional BCL11B mutation causes human multisystem anomalies with SCID, while also revealing a novel, pre-thymic role for Bcl11b in hematopoietic progenitors.
2016-07-29 | GSE84941 | GEO
Project description:Comparison of whole genome exome array CGH to a commercial SNP array for detection of de novo and homozygous copy number variants in 99 autism simplex trios. Will update once manuscript is prepared.
2011-04-30 | GSE23765 | GEO
Project description:Oocyte defects lie at the heart of some forms of infertility and could potentially be addressed therapeutically by alternative routes for oocyte formation. Here, we describe the generation of functional human oocytes following nuclear transfer of first polar body (PB1) genomes from metaphase II (MII) oocytes into enucleated donor MII cytoplasm (PBNT). The reconstructed oocytes supported the formation of de novo meiotic spindles and, after fertilization with sperm, meiosis completion and formation of normal diploid zygotes. While PBNT zygotes developed to blastocysts less frequently (42%) than controls (75%), genome-wide genetic, epigenetic, and transcriptional analyses of PBNT and control ESCs indicated comparable numbers of structural variations and markedly similar DNA methylation and transcriptome profiles. We conclude that rescue of PB1 genetic material via introduction into donor cytoplasm may offer a source of oocytes for infertility treatment or mitochondrial replacement therapy for mtDNA disease.
2016-12-07 | GSE79309 | GEO
Project description:Oocyte defects lie at the heart of some forms of infertility and could potentially be addressed therapeutically by alternative routes for oocyte formation. Here, we describe the generation of functional human oocytes following nuclear transfer of first polar body (PB1) genomes from metaphase II (MII) oocytes into enucleated donor MII cytoplasm (PBNT). The reconstructed oocytes supported the formation of de novo meiotic spindles and, after fertilization with sperm, meiosis completion and formation of normal diploid zygotes. While PBNT zygotes developed to blastocysts less frequently (42%) than controls (75%), genome-wide genetic, epigenetic, and transcriptional analyses of PBNT and control ESCs indicated comparable numbers of structural variations and markedly similar DNA methylation and transcriptome profiles. We conclude that rescue of PB1 genetic material via introduction into donor cytoplasm may offer a source of oocytes for infertility treatment or mitochondrial replacement therapy for mtDNA disease.
2016-12-07 | GSE79300 | GEO