Ontology highlight
ABSTRACT:
PROVIDER: PRJNA172961 | ENA |
REPOSITORIES: ENA
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Project description:Multiple replication abnormalities cause cells lacking BRCA2 to enter mitosis with under-replicated DNA and to activate mitotic DNA synthesis (MiDAS). However, the precise position of these MiDAS sites, as well as their origin, remains unknown. Here we labelled mitotic nascent DNA and performed high-throughput sequencing to identify at high-resolution the sites where MiDAS occurs in the absence of BRCA2. This approach revealed 150 genomic loci affected by MiDAS, which map within regions replicating during early S-phase and are therefore distinct from the aphidicolin-induced common fragile sites. Moreover, these sites largely localise near early firing origins and within genes transcribed in early S, suggesting that they stem from transcription-replication conflicts (TCRs). Inhibiting transcription with 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) during early S-phase abrogates MiDAS. Strikingly, MiDAS sites co-localise with genomic loci where R-loops form in unchallenged conditions, suggesting that R-loop accumulation caused by BRCA2 inactivation leads to DNA lesion which are repaired by MiDAS. RAD52 is required in this process, as its abrogation in BRCA2-deficient cells reduces the rate of MiDAS and causes DNA damage accumulation in G1. Furthermore, MiDAS sites triggered by BRCA2 inactivation are hotspots for genomic rearrangement in BRCA2-mutated breast tumours. These results indicate that BRCA2 acts in early S-phase to protect TRC- and R-loop-induced DNA lesions, thereby preventing them from becoming a source of genomic instability and tumorigenesis.
2022-08-01 | GSE196163 | GEO
Project description:East African cichlid fishes have radiated in an explosive fashion. The (epi)genetic basis for the abundant phenotypic diversity of these fishes remains largely unknown. As transposable elements (TEs) contribute extensively to genome evolution, we reasoned that TEs may have fuelled cichlid radiations. While TE-derived genetic and epigenetic variability has been associated with phenotypic traits, TE expression and epigenetic silencing remain unexplored in cichlids. Here, we profiled TE expression in African cichlids, and describe dynamic expression patterns during embryogenesis and according to sex. Most TE silencing factors are conserved and expressed in cichlids. We describe an expansion of two truncated Piwil1 genes in Lake Malawi/Nyasa cichlids, encoding a Piwi domain with catalytic potential. To further dissect epigenetic silencing of TEs, we focused on small RNA-driven epigenetic silencing. We detect a small RNA population in gonads consistent with an active Piwi-interacting RNA (piRNA) pathway targeting TEs. We uncover fluid genomic origins of piRNAs in closely related cichlid species. This, along with signatures of positive selection in piRNA pathway factors, points towards fast co-evolution of TEs and the piRNA pathway. Our study is the first step to understand the contribution of ongoing TE-host arms races to the cichlid radiations in Africa.
2024-04-02 | PXD047439 | Pride
Project description:East African cichlid fishes have diversified in an explosive fashion, but the (epi)genetic basis of the phenotypic diversity of these fishes remains largely unknown. Although transposable elements (TEs) have been associated with phenotypic variation in cichlids, little is known about their transcriptional activity and epigenetic silencing. Here, we describe dynamic patterns of TE expression in African cichlid gonads and during early development. Orthology inference revealed an expansion of piwil1 genes in Lake Malawi cichlids, likely driven by PiggyBac TEs. The expanded piwil1 copies have signatures of positive selection and retain amino acid residues essential for catalytic activity. Furthermore, the gonads of African cichlids express a Piwi-interacting RNA (piRNA) pathway that target TEs. We define the genomic sites of piRNA production in African cichlids and find divergence in closely related species, in line with fast evolution of piRNA-producing loci. Our findings suggest dynamic co-evolution of TEs and host silencing pathways in the African cichlid radiations. We propose that this co-evolution has contributed to cichlid genomic diversity.
2024-04-01 | GSE252804 | GEO
Project description:Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor CCAAT enhancer binding protein beta (C/EBPβ) are expressed from a single intronless Cebpb gene by alternative translation initiation. Isoform expression is sensitive to mammalian target of rapamycin (mTOR)-mediated activation of the translation initiation machinery and relayed through an upstream open reading frame (uORF) on the C/EBPβ mRNA. The truncated C/EBPβ LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBPβ LIP may function as an oncogene. In this study, we examined spontaneous tumor formation in C/EBPβ knockin mice that constitutively express only the C/EBPβ LIP isoform from its own locus. Our data show that deregulated C/EBPβ LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBPβ LIP supports a protumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation reinitiation of C/ EBPβ LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBPβ LIP isoform.
2014-12-16 | GSE53770 | GEO
Project description:DNA replication stress is an established driver of cancer-associated chromosomal rearrangements. Replication stress perturbs the duplication of late-replicating loci and activates a mitotic DNA repair pathway (termed MiDAS) for completion of replication. We here investigated RAD51-independent MiDAS.
2022-06-27 | GSE196278 | GEO
Project description:BACKGROUND & AIMS: C/EBPbeta is involved in numerous process as carcinogenesis but its role is still not clear due to the existence of an active form (LAP) and an inhibitory form (LIP) of this transcription factor. The main goals of the present research were (i) the identification of genes inversely regulated by LAP and LIP i-e the genuine C/EBPbeta molecular signature in the Hep3B human hepatoma cell line (ii) a better understanding of LAP and LIP respective role in hepatic cells survival and proliferation (iii) the search of the C/EBPbeta signature among hepatocellular carcinomas. METHODS: Using Tet-off expression system we engineered Hep3BLAP and Hep3BLIP cells, in which LAP and LIP were over-expressed respectively. Then, using both expression profiling (DNA arrays) and ChIP-on-chip analysis, we identified genes inversely and/or directly regulated by each of the C/EBPbeta isoforms. The expression levels of these genes regulated by LAP/LIP were compared in controls and HCCs patients. RESULTS: We identified 676 genes inversely regulated by LAP and LIP and among these, 45 are direct targets. Using functional studies, we displayed the opposite role of LAP and LIP in staurosporine-induced cell death and the implication of LAP in the repression of Hep3B cells proliferation. Finally we identified a subgroup of HCCs with a deregulation of 165 genes belonging to C/EBPbeta signature and coding for proteins involved in chemoresistance and metastasis formation. CONCLUSIONS: Our study increases knowledge on LAP and LIP functions and provides first evidence that their molecular signature in the HCCs could predict tumor evolution.
2009-02-27 | GSE15010 | GEO
Project description:Microarray analysis of gene expression in the olfactory epithelium of macrophage depleted mice to study the role of macrophages in regulating neurodegeneration, neuroprotection, and neurogenesis of olfactory sensory neurons Keywords: comparison of gene expression level in sham and 48 hr OBX Lip-O mice versus Lip-C mice
2007-12-14 | GSE6540 | GEO
Project description:Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor CCAAT enhancer binding protein beta (C/EBPM-NM-2) are expressed from a single intronless Cebpb gene by alternative translation initiation. Isoform expression is sensitive to mammalian target of rapamycin (mTOR)-mediated activation of the translation initiation machinery and relayed through an upstream open reading frame (uORF) on the C/EBPM-NM-2 mRNA. The truncated C/EBPM-NM-2 LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBPM-NM-2 LIP may function as an oncogene. In this study, we examined spontaneous tumor formation in C/EBPM-NM-2 knockin mice that constitutively express only the C/EBPM-NM-2 LIP isoform from its own locus. Our data show that deregulated C/EBPM-NM-2 LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBPM-NM-2 LIP supports a protumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation reinitiation of C/ EBPM-NM-2 LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBPM-NM-2 LIP isoform. A cohort of C/EBPb LIP heterozygous (+/L) and wild type (+/+) mice were kept over 25 months and animals showing palpable lymphoma were sacrificed. The lymphoma developed spontaneously. For each genotype, 5 lymphoma were used for RNA preparation and gene expression profiling analysis.
2014-12-16 | E-GEOD-53770 | biostudies-arrayexpress
Project description:This study examines genomic copy-number variation among African cichlids spanning multiple tribes and radiations. We map CNVs and hotspots throughout the Oreochromis niloticus reference genome, categorize gene ontology enrichment within CNV regions, and compare results with sequence-based cichlid phylogenies.
2019-07-26 | GSE117914 | GEO
Project description:East African cichlid fishes have diversified in an explosive fashion, but the (epi)genetic basis of the phenotypic diversity of these fishes remains largely unknown. Although transposable elements (TEs) have been associated with phenotypic variation in cichlids, little is known about their transcriptional activity and epigenetic silencing. Here, we describe dynamic patterns of TE expression in African cichlid gonads and during early development. Orthology inference revealed an expansion of piwil1 genes in Lake Malawi cichlids, likely driven by PiggyBac TEs. The expanded piwil1 copies have signatures of positive selection and retain amino acid residues essential for catalytic activity. Furthermore, the gonads of African cichlids express a Piwi-interacting RNA (piRNA) pathway that target TEs. We define the genomic sites of piRNA production in African cichlids and find divergence in closely related species, in line with fast evolution of piRNA-producing loci. Our findings suggest dynamic co-evolution of TEs and host silencing pathways in the African cichlid radiations. We propose that this co-evolution has contributed to cichlid genomic diversity.
2024-04-01 | GSE252805 | GEO