A Metabolic Regulatory Network for the C. elegans Intestine
Ontology highlight
ABSTRACT:
ORGANISM(S): Caenorhabditis elegans
PROVIDER: GSE199433 | GEO | 2022/06/16
REPOSITORIES: GEO
Similar Datasets
Project description:The regulation of metabolism is vital to any organism. One mechanism of this regulation is by transcriptionally activating or repressing genes encoding metabolic enzymes and transporters. This is used to wire tissue-relevant metabolic networks during development, but also to rewire metabolism upon nutritional or genetic perturbations. While many individual examples of transcriptional regulation of metabolism have been reported, a systems-level study of how metabolic gene expression responds to such perturbations is lacking in any animal. Here, we apply worm perturb-seq (WPS), a high-throughput, whole-animal RNAi/RNA-seq method, on ~900 metabolic genes in the nematode Caenorhabditis elegans, to derive a metabolic gene regulatory network (mGRN) in which the knockdown of 365 metabolic genes is connected to 9,414 differentially expressed genes (DEGs) by more than 110,000 interactions. The mGRN has a highly modular structure in which distinct 22 perturbation clusters connect to 44 co-regulated gene expression programs. We uncover widespread yet highly specific responses in genes associated with stress responses and food digestion, along with various modes of transcriptional changes from simple ‘within pathway’ to complex ‘network coordination’. By integrating the mGRN with metabolic network modeling, we elucidate an underlying designing principle of transcriptional rewiring that leads us to propose a ‘compensation/repression model’ in which high-level, core metabolic functions regulate each other, likely to maintain animal homeostasis.
2024-11-20 | GSE253847 | GEO
Project description:During tumor progression, cancer cells rewire their metabolism to face their bioenergetic demands. In recent years, microRNAs (miRNAs) have emerged as regulatory elements that inhibit the translation and stability of crucial mRNAs, some of them causing direct metabolic alterations in cancer. In this study, we investigated the relationship between miRNAs and their targets mRNAs that control metabolism, and how this fine-tuned regulation is diversified depending on the tumor stage. To do so, we implemented a paired analysis of RNA-seq and small RNA-seq in a breast cancer cell line (MCF7). The cell line was cultured in multicellular tumor spheroid (MCTS) and monoculture conditions. For MCTS, we selected two-time points during their development to recapitulate a proliferative and quiescent stage and contrast their miRNA and mRNA expression patterns associated with metabolism. As a result, we identified a set of new direct putative regulatory interactions between miRNAs and metabolic mRNAs representative for proliferative and quiescent stages. Notably, our study allows us to suggest that miR-3143 regulates the carbon metabolism by targeting hexokinase-2. Also, we found that the overexpression of several miRNAs could directly overturn the expression of mRNAs that control glycerophospholipid and N-Glycan metabolism. While this set of miRNAs downregulates their expression in the quiescent stage, the same set is upregulated in proliferative stages. This last finding suggests an additional metabolic switch of the above mentioned metabolic pathways between the quiescent and proliferative stages. Our results contribute to a better understanding of how miRNAs modulate the metabolic landscape in breast cancer MCTS, which eventually will help to design new strategies to mitigate cancer phenotype.
2020-11-11 | E-MTAB-9741 | biostudies-arrayexpress
Project description:Nuclear RNAi in C. elegans induces a set of transgenerationally heritable marks of H3K9me3, H3K23me3, and H3K27me3 at the target genes. The function of H3K23me3 in the nuclear RNAi pathway is largely unknown due to the limited knowledge of H3K23 histone methyltransferase (HMT). In this study we identified SET-21 as a novel H3K23 HMT. By taking combined genetic, biochemical, and genomic approaches we found that SET-21 functions synergistically with a previously reported H3K23 HMT SET-32 to deposit H3K23me3 at the native targets of germline nuclear RNAi. We identified a subset of nuclear RNAi targets that became transcriptionally activated in the set-21;set-32 double mutant. SET-21 and SET-32 are also required for a robust transgenerational gene silencing induced by exogenous dsRNA. The set-21;set-32 double mutant exhibited an enhanced mortal germline phenotype at a high temperature compared to the set-32 single mutant. Together, these results support a model in which H3K23 HMTs SET-21 and SET-32 function cooperatively to ensure the robustness of germline nuclear RNAi and promotes the germline immortality under the heat stress.
2024-12-06 | PXD052034 | Pride
Project description:Background: Disruptions of 3D chromatin architecture can alter the activity of topologically associated domains (TADs), rewire enhancer-promoter interactions and thus significantly impact gene regulatory programs. Recently, such disruptions have been implicated in tumorigenesis, highlighting the need for a deeper understanding of their detailed role. Methods: T-ALL primary samples and prototypical cell lines as well as healthy T cell counterparts were profiled by in-situ Hi-C, RNA-Seq and CTCF ChIP-Seq. Data was subsequently integrated. Results: Our studies showed that the genome of leukemia cells does not display global changes in TAD structures but presents local changes in selected TAD boundaries as well as alterations of intra-TAD activity which are associated with changes in gene expression of key oncogenes and tumor suppressors, strong correlation with CTCF-mediated insulation and enhancer activity. Finally, we showed that 3D interactions on selected loci can be partially corrected pharmacologically, potentially accounting for the anti-leukemogenic effects of these drugs. Conclusions: Our studies underscore the need for further investigation of factors that rewire long range interactions especially during tumorigenesis, as they could be targets for pharmacological targeting.
2019-08-04 | GSE134762 | GEO
Project description:Background: Disruptions of 3D chromatin architecture can alter the activity of topologically associated domains (TADs), rewire enhancer-promoter interactions and thus significantly impact gene regulatory programs. Recently, such disruptions have been implicated in tumorigenesis, highlighting the need for a deeper understanding of their detailed role. Methods: T-ALL primary samples and prototypical cell lines as well as healthy T cell counterparts were profiled by in-situ Hi-C, RNA-Seq and CTCF ChIP-Seq. Data was subsequently integrated. Results: Our studies showed that the genome of leukemia cells does not display global changes in TAD structures but presents local changes in selected TAD boundaries as well as alterations of intra-TAD activity which are associated with changes in gene expression of key oncogenes and tumor suppressors, strong correlation with CTCF-mediated insulation and enhancer activity. Finally, we showed that 3D interactions on selected loci can be partially corrected pharmacologically, potentially accounting for the anti-leukemogenic effects of these drugs. Conclusions: Our studies underscore the need for further investigation of factors that rewire long range interactions especially during tumorigenesis, as they could be targets for pharmacological targeting.
2019-08-04 | GSE134761 | GEO
Project description:Background: Disruptions of 3D chromatin architecture can alter the activity of topologically associated domains (TADs), rewire enhancer-promoter interactions and thus significantly impact gene regulatory programs. Recently, such disruptions have been implicated in tumorigenesis, highlighting the need for a deeper understanding of their detailed role. Methods: T-ALL primary samples and prototypical cell lines as well as healthy T cell counterparts were profiled by in-situ Hi-C, RNA-Seq and CTCF ChIP-Seq. Data was subsequently integrated. Results: Our studies showed that the genome of leukemia cells does not display global changes in TAD structures but presents local changes in selected TAD boundaries as well as alterations of intra-TAD activity which are associated with changes in gene expression of key oncogenes and tumor suppressors, strong correlation with CTCF-mediated insulation and enhancer activity. Finally, we showed that 3D interactions on selected loci can be partially corrected pharmacologically, potentially accounting for the anti-leukemogenic effects of these drugs. Conclusions: Our studies underscore the need for further investigation of factors that rewire long range interactions especially during tumorigenesis, as they could be targets for pharmacological targeting.
2019-08-04 | GSE115895 | GEO
Project description:Background: Disruptions of 3D chromatin architecture can alter the activity of topologically associated domains (TADs), rewire enhancer-promoter interactions and thus significantly impact gene regulatory programs. Recently, such disruptions have been implicated in tumorigenesis, highlighting the need for a deeper understanding of their detailed role. Methods: T-ALL primary samples and prototypical cell lines as well as healthy T cell counterparts were profiled by in-situ Hi-C, RNA-Seq and CTCF ChIP-Seq. Data was subsequently integrated. Results: Our studies showed that the genome of leukemia cells does not display global changes in TAD structures but presents local changes in selected TAD boundaries as well as alterations of intra-TAD activity which are associated with changes in gene expression of key oncogenes and tumor suppressors, strong correlation with CTCF-mediated insulation and enhancer activity. Finally, we showed that 3D interactions on selected loci can be partially corrected pharmacologically, potentially accounting for the anti-leukemogenic effects of these drugs. Conclusions: Our studies underscore the need for further investigation of factors that rewire long range interactions especially during tumorigenesis, as they could be targets for pharmacological targeting.
2019-08-04 | GSE115893 | GEO
Project description:Background: Disruptions of 3D chromatin architecture can alter the activity of topologically associated domains (TADs), rewire enhancer-promoter interactions and thus significantly impact gene regulatory programs. Recently, such disruptions have been implicated in tumorigenesis, highlighting the need for a deeper understanding of their detailed role. Methods: T-ALL primary samples and prototypical cell lines as well as healthy T cell samples were profiled by in-situ Hi-C, RNA-Seq, CTCF ChIP-Seq and suuported by matching WGS of three primary T-ALL samples. Data was subsequently integrated. Results: Our studies showed that the genome of leukemia cells does not display global changes in TAD structures but presents local changes in selected TAD boundaries as well as alterations of intra-TAD activity which are associated with changes in gene expression of key oncogenes and tumor suppressors, strong correlation with CTCF-mediated insulation and enhancer activity. Finally, we showed that 3D interactions on selected loci can be partially corrected pharmacologically, potentially accounting for the anti-leukemogenic effects of these drugs. Conclusions: Our studies underscore the need for further investigation of factors that rewire long range interactions especially during tumorigenesis, as they could be targets for pharmacological targeting.
2019-10-29 | GSE139449 | GEO
Project description:Signal-dependent RNA Polymerase II (Pol2) productive elongation is an integral component of gene transcription, including those of immediate early genes (IEGs) induced by neuronal activity. However, it remains unclear how productively elongating Pol2 overcome nucleosomal barriers. Using RNAi, three degraders, and several small molecule inhibitors, we show that the mammalian SWI/SNF complex of neurons (neuronal BAF, or nBAF) is required for activity-induced transcription of neuronal IEGs, including Arc. The nBAF complex facilitates promoter-proximal Pol2 pausing, signal-dependent Pol2 recruitment (loading), and importantly, mediates productive elongation in the gene body via interaction with the elongation complex and elongation-competent Pol2. Mechanistically, Pol2 elongation is mediated by activity-induced nBAF assembly (especially, ARID1A recruitment) and its ATPase activity. Together, our data demonstrate that the nBAF complex regulates several aspects of Pol2 transcription and reveal mechanisms underlying activity-induced Pol2 elongation. These findings may offer insights into human maladies etiologically associated with mutational interdiction of BAF functions.
2024-06-18 | PXD052840 | JPOST Repository
Project description:Mammals have one Dicer gene required for biogenesis of small RNAs in microRNA (miRNA) and RNA interference (RNAi) pathways. Yet, endogenous RNAi is highly active in oocytes but not in somatic cells. Here, we provide a mechanistical explanation for high RNAi activity in mouse oocytes. The main Dicer isoform in oocytes is transcribed from an intronic MT-C retrotransposon, which functions as a promoter of an oocyte-specific Dicer isoform (denoted DicerO). DicerO lacks an N-terminal helicase domain and has a higher cleavage activity than the full-length Dicer from somatic cells. DicerO can rescue the miRNA pathway and, in addition, it efficiently produces small RNAs from long dsRNA substrates. Thus, control of endogenous RNAi activity in mice occurs via alternative Dicer isoform and the phylogenetic origin of DicerO demonstrates evolutionary plasticity of RNA silencing pathways.
2013-11-07 | GSE41207 | GEO