Childhood cancer mutagenesis caused by a domesticated DNA transposase
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE249785 | GEO | 2024/03/27
REPOSITORIES: GEO
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Project description:The study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. We used single-cell transcriptomics to study >60,000 cells from the developing murine cerebellum, and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. Sonic Hedgehog medulloblastoma transcriptionally mirrors the granule cell hierarchy as expected, whereas Grp3-MB resemble Nestin+ve stem cells, Group 4 medulloblastomas resemble unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the pre-natal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development, and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.
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Project description:Proteins encoded by transposable elements (TEs) play a vital role in their proliferation in host genomes. In recent years, an increasing number of studies have shown that TE proteins have contributed to the emergence of novel host proteins. In Drosophila, there are several proteins derived from the PIF/Harbinger transposase superfamily called Drosophila PIF Like Genes (DPLGs). Here, we investigated the function of four DPLGs (DPLG1-4) in D. melanogaster that are highly conserved and present across Drosophila but are deeply diverged from each other, and likely originated through independent domestication of the transposase from distinct PIF-like TE families. We have analyzed transcript localization of DPLG 1-4, tagged DPLG3 and DPLG4 and studied their protein localization and, produced null alleles for DPLG1 and DPLG4. RNA in situ hybridization reveals that DPLG1-4 have strikingly similar pattern of transcript localization in the gonads, and in the nervous system during embryogenesis, suggesting their domestication for related functions. DPLGs show co-expression enrichment with transcription factors in ovaries and during embryogenesis supporting that they may be domesticated as regulatory proteins in flies. DPLG3 and DPLG4 tagged proteins localize with DNA in the nucleus of the ovaries consistent with this hypothesis. Loss of DPLG1 or DPLG4 results in viability and/or fertility effects, while loss of both DPLG1 and DPLG4 resulted in no effect in viability or fertility suggesting genetic interaction between these two genes. Further, loss of DPLG4 showed increased survival in flies, and increased fertility in older females indicating its involvement in the process of ageing. Transcriptional analyses in the ovaries showed that the loss of either DPLG1 or DPLG4 protein leads to modest changes in transcription of a large and significantly overlapping set of genes, and also affects transposable elements activity. The observed functional overlap of independently domesticated transposases from the same TE family and genetic interaction between them suggests a stepping stone model in which domestication of a PIF/Harbinger transposase might promote the domestication of related transposases for gonad and nervous system regulatory functions.
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Project description:Deep sequencing of single cell-derived genomic DNA and/or cDNAs brings novel insights into oncogenesis and embryogenesis. However, traditional library preparation for RNA-Seq requires multiple steps, including shearing the target DNA/RNA and following sequential enzymatic reactions, which result in consequent sample loss and stochastic variation at each step. Such variation may significantly affect the output from sequencing. We have found that a new technique of library preparation using hyperactive Tn5 transposase for the next-generation sequencer of Illumina's platform provided high-quality libraries from 100ng of short-length (average 700~800 bp) single-cell level cDNA. This new method reduced the number of steps in the protocol, which resulted in improved reproducibility and reduced variation among the specimens. Two methods of library preparation (sonication, tagmentation with hyperactive Tn5 transposase) were compared in the case of RNA-Seq for single-cell level cDNA. Technical triplicates were used.
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Project description:A 44K salmonid oligoarray was used to examine the influence of genotype and developmental stage on mRNA expression in wild-type (age matched and size matched to domesticated), domesticated and wild-domesticated hybrid populations. Significant differences were found in mRNA expression between genotypes. The largest proportion of differentially expressed mRNAs were found in comparisons of domesticated and wild-type groups. Significant differences were also noted in pairings of wild-domesticated hybrid progeny to both parental strains. Differences in gene expression were found in comparison of both wild-type age and size matched to each other and in combination with genotype analysis, showing a strong effect of fish developmental stage on differential gene expression. Domestication was found to modify biological pathways associated with transport, metabolism, cell tissue structure and development, stress and immune response and protein synthesis. Genotype analysis of hybrid progeny inheritance patterns showed similar levels of recessive, dominant and additive effects.
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