Inversion breakpoints in Drosophila
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB23256 | ENA |
REPOSITORIES: ENA
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Project description:Despite advances in nuclease-based genome editing technologies, correcting human disease-causing genomic inversions remains a challenge. Here, we describe the potential use of a recombinase-based system to correct a 140 kb int1h inversion frequently found in patients diagnosed with Hemophilia A. With the use of directed molecular evolution, we developed a linked heterodimeric recombinase system (RecF8) achieving 30% inversion of the target sequence in human tissue culture cells. Transient RecF8 treatment of endothelial cells, differentiated from int1h patient derived iPSCs, resulted in prominent correction of the inversion and restored Factor VIII mRNA expression. Our data suggest that the development of designer-recombinases represent an efficient and specific mean towards treatment of large gene inversions causing monogenic diseases.
2021-12-31 | GSE159492 | GEO
Project description:The hematopoietic system is maintained throughout life by hematopoietic stem cells that are capable of differentiation to all hematopoietic lineages. An intimate balance between self-renewal, differentiation, and quiescence is required to maintain hematopoiesis. Disruption of this balance can result in hematopoietic malignancy, including acute myeloid leukemia (AML). FBXO9, from the F-box ubiquitin E3 ligases, is down-regulated in patients with AML compared to normal bone marrow. FBXO9 is a substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex. FBXO9 is highly expressed in hematopoietic stem and progenitor populations, which contain the tumor-initiating population in AML. In AML patients, decrease in FBXO9 expression is most pronounced in patients with the inversion of chromosome 16 (Inv(16)), a rearrangement that generates the transcription factor fusion gene, CBFB-MYH11. To study FBXO9 in malignant hematopoiesis, we generated a conditional knockout mouse model using a novel CRISPR/Cas9 strategy. Our data shows that deletion of Fbxo9 in mice expressing Cbfb-MYH11 leads to markedly accelerated and aggressive leukemia development. In addition, we find loss of FBXO9 leads to increased proteasome expression and tumors are more sensitive to bortezomib suggesting that FBXO9 expression may predict patient response to bortezomib treatment.
2019-11-27 | PXD014387 | Pride
Project description:How modification of gene expression generates novel traits is key to understanding the evolutionary process. Here we investigated the genetic basis for the origin of the piscine gas bladder from lungs of ancestral bony vertebrates. Distinguishing these homologous organs is the direction of budding from the foregut during development; lungs bud ventrally and the gas bladder buds dorsally. We investigated whether this morphological inversion is associated with the molecular inversion of conserved genes regulating lung and gas bladder development. Using laser-capture microdissection and RNA-seq, we assayed transcript abundance and compared expression patterns between dorsal and ventral foregut tissues at three developmental stages spanning gasbladder development. Our focal taxon, bowfin (Amia calva), representing the sistergroup to teleosts, is an early diverging ray-finned fish with a gas bladder. We discovered a number of genes with unknown function during lung development that are differentially expressed during gas bladder development and annotated to functions relevant for organ budding. We also identified several known lung-regulatory genes that exhibit inverted dorsoventral expression during gasbladder development relative to lung development. In particular, we found Tbx5 is strongly expressed in the dorsal mesoderm surrounding the gas bladder during bowfin development, and several interacting genes are co-expressed dorsally with Tbx5. In contrast, in mouse and bichir (Polypterus senegalus), the only ray-finned fish that have lungs, Tbx5 is expressed in the ventral lung mesoderm during lung development. Our data demonstrating dorsoventral inversion of conserved genes suggest that these genes may have contributed to the evolutionary transition between ventral lungs and a dorsal gas bladder in ray-finned fishes.
2021-05-12 | GSE152992 | GEO
Project description:Aging is a time-dependent biological phenomenon governed by complex networks of regulatory components and their transitions over lifetime. Yet, there have been limited efforts to pin down age-associated networks and map their dynamic characteristics onto aging phenotypes. Here, we built time-course genetic regulatory networks of NAM/ATAF/CUC (NAC) transcription factors during the course of leaf aging in Arabidopsis, using causal regulatory relationships among NACs identified from mutants of 49 aging-associated NACs. These temporal networks revealed a regulatory inversion from activating to repressive regulatory modes at a pre-senescent stage. The inversion was governed by three hub NACs, and their mutants conferred earlier aging with altered expression of reactive oxygen species and salicylic acid response genes. Overexpression of the hub NACs delayed the regulatory inversion, rendering delayed age-dependent cell death. We conclude that the regulatory inversion in NAC networks at a pre-senescent stage directs when age-dependent cell death should proceed in plants.
2018-04-29 | GSE92369 | GEO
Project description:Aging is a time-dependent biological phenomenon governed by complex networks of regulatory components and their transitions over lifetime. Yet, there have been limited efforts to pin down age-associated networks and map their dynamic characteristics onto aging phenotypes. Here, we built time-course genetic regulatory networks of NAM/ATAF/CUC (NAC) transcription factors during the course of leaf aging in Arabidopsis, using causal regulatory relationships among NACs identified from mutants of 49 aging-associated NACs. These temporal networks revealed a regulatory inversion from activating to repressive regulatory modes at a pre-senescent stage. The inversion was governed by three hub NACs, and their mutants conferred earlier aging with altered expression of reactive oxygen species and salicylic acid response genes. Overexpression of the hub NACs delayed the regulatory inversion, rendering delayed age-dependent cell death. We conclude that the regulatory inversion in NAC networks at a pre-senescent stage directs when age-dependent cell death should proceed in plants.
2018-04-29 | GSE92314 | GEO
Project description:The genome of the white-throated sparrow (Zonotrichia albicollis) contains an inversion polymorphism on chromosome 2 that is linked to predictable variation in a suite of phenotypic traits including plumage color, aggression, and parental behavior. Differences in gene expression between the two color morphs, which represent the two common inversion genotypes (ZAL2/ZAL2 and ZAL2/ZAL2m), are therefore of potential interest toward understanding the molecular underpinnings of these phenotypes. To identify genes that are differentially expressed between the two morphs and correlated with behavior, we quantified both behavior and gene expression in a population of free-living white-throated sparrows. We quantified behavioral responses to simulated territorial intrusions (STIs) early during the breeding season. In the same birds, we then performed a transcriptomewide analysis of gene expression in two behaviorally relevant brain regions, the medial amygdala and hypothalamus. Using network analyses, we identified modules of genes that were correlated with both morph and STI-induced singing behavior. The majority of these genes were located within the inversion, demonstrating the profound effect the inversion has on the expression of genes captured by the rearrangement. Gene pathway analyses revealed that in the medial amygdala, the most prominent pathways were those related to steroid hormone receptor activity. Within these pathways, the only gene encoding such a receptor was ESR1 (estrogen receptor alpha). Our results thus suggest that ESR1 and related genes are important for behavioral differences between the morphs.
2017-11-06 | GSE77186 | GEO
Project description:CTCF/cohesin play a central role in insulator function and higher-order chromatin organization of mammalian genomes. Recent studies identified a correlation between the orientation of CTCF-binding sites (CBSs) and chromatin loops. To test the functional significance of this observation, we combined CRISPR/Cas9-based genomic-DNA-fragment editing with chromosome-conformation-capture experiments to show that the location and relative orientations of CBSs determine the specificity of long-range chromatin looping in mammalian genomes, using protocadherin (Pcdh) and β-globin as model genes. Inversion of CBS elements within the Pcdh enhancer reconfigures the topology of chromatin loops between the distal enhancer and target promoters, and alters gene-expression patterns. Thus, although enhancers can function in an orientation-independent manner in reporter assays, in the native chromosome context the orientation of at least some enhancers carrying CBSs can determine both the architecture of topological chromatin domains and enhancer/promoter specificity. The findings reveal how 3D chromosome architecture can be encoded by genome sequence.
2015-08-13 | GSE71275 | GEO
Project description:Phenotypic evolution can result from gains and losses of genes, mutations in coding sequences, or regulatory mutations affecting gene expression. While the relative importance of these mechanisms is debated, regulatory evolution is recognized as a key driver of phenotypic diversity. In this study, we applied a phylogenetic model to discretized gene expression states (active or inactive) to investigate the evolutionary turnover of organ-specific transcriptomes, which we define as instances where gene expression is activated or deactivated in a particular organ. We focus on transcriptome turnover in two male reproductive organs in 11 species of the Drosophila melanogaster species group. Using the Bayesian inference method zigzag (Thompson et al. 2020), we estimate that testes express a higher proportion of the genome (65--75% of genes, depending on the species) compared to accessory glands (46--64%), with background expression noise producing less than 1% of transcripts in both organs. We find that many conserved genes have gained or lost expression in testes and accessory glands. Our model of joint transcriptome evolution, applied to 8,660 genes conserved as single copy families in all species (singleton genes), revealed similar turnover rates but distinct evolutionary trajectories in the two organs. We estimate that the genes in our data set transition between active and inactive expression states at rates on the order of 10^-9 yr^-1. The two organs experienced accelerated transcriptome turnover on different branches of the Drosophila phylogeny. The accessory glands exhibit greater variation in turnover rates among lineages, suggesting a lower baseline rate with bursts of rapid evolution in a subset of branches on the phylogeny. We do not observe significant differences in turnover rates between X-linked and autosomal genes. Genes that encode transcription factors transition between active and inactive states slower than non-TF genes in the accessory gland, but slightly faster in the testis. The results are robust to the choice of probability cut-offs used to discretize gene expression states, and there is good agreement between the estimates of expression states from zigzag and the inferences from the phylogenetic model. Overall, our study highlights the complex dynamics of transcriptome evolution in male reproductive organs. We discuss the benefits and challenges associated with investigating the evolution of gene expression as a binary trait and suggest potentially fruitful avenues for further methodological development.
2024-10-15 | GSE274048 | GEO
Project description:To investigate the changes in proteins, metabolites, and related mechanisms in the Q7 hypothalamus of pregnant rats after circadian rhythm inversion during the whole pregnancy cycle
2022-06-26 | PXD034926 |