Project description:Aneuploidy is a frequent feature of human tumors. Germline mutations leading to aneuploidy are very rare in humans, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, the gene encoding the Spindle Assembly Checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias, including five malignant tumors. Functional studies in peripheral blood cells demonstrated lack of full-length protein and deficient SAC response, resulting in ~30-40% of aneuploid cells as detected by cytogenetic and single-cell (sc) DNA analysis. scRNA-seq analysis of proband blood cells identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFkB signaling. The inference of chromosomal aberrations from scRNA-seq analysis detected inflammatory signals both in aneuploid and euploid cells, suggesting a non-cell autonomous response to aneuploidy. In addition to random aneuploidies, MAD1L1 mutations resulted in specific clonal expansions of T-cells with chromosome 18 gains and enhanced cytotoxic profile, as well as intermediate B-cells with chromosome 12 gains and transcriptomic signatures characteristic of chronic lymphocytic leukemia cells. These data point to MAD1L1 mutations as the cause of a new variant of mosaic variegated aneuploidy syndrome (MVA) with systemic inflammation and unprecedented tumor susceptibility.
Project description:We report single-cell RNA-sequencing data for sexed D. melanogaster germ cells from 0-8h embryos. We find in this time window that the transcriptome of male and female germ cells diverge and this coincides with the activation of the zygotic germline genome.
Project description:Male and female germline stem cells are critical for passing genetic information from generation to generation. Accumulating evidences indicate that long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) play important roles in self-renewal and differentiation of germline stem cells. However, the mechanisms remain largely unknown. In this study, we explored the mRNAs, lncRNAs and circRNAs expression profiles of male and female germline stem cells through high-throughput sequencing.
Project description:The maintenance and differentiation of highly potent animal stem cells generates an epigenetic cycle that underlies development. Drosophila female germline stem cells (GSC) produce cystoblast daughters that differentiate into nurse cells and oocytes. Developmental chromatin analysis profiling the differentiation of GSCs into cystoblasts and NCs of increasing ploidy shows that cystoblasts start developing by forming heterochromatin while in a transient syncytial state, the germline cyst, reminiscent of early embryonic cells. The open GSC chromatin state is further restricted by Polycomb repression of targets that include testis expressed genes briefly active in early female germ cells. Like other highly potent stem cells, GSC metabolism is reprogrammed and Myc-dependent growth is upregulated by altering mitochondrial membrane transport, gluconeogenesis and other processes. Thus, the animal generational cycle comprises similar but distinct maternal and zygotic stem cell epigenetic cycles. We propose that the pluripotent stem cell state and daughter cell differentiation were shaped by the pressure to resist transposon activity over evolutionary time scales. In this GEO submission, we present data and analyses pertaining to H3K27ac, H3K27me3, and H3K9me3 ChIPseq, ATACseq, and RNAseq of Germline Stem Cells (GSCs) and Nurse Cells (NCs) from Drosophila melanogaster ovaries.