scholarly journals Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer

2018 ◽  
Author(s):  
Anna S. Trigos ◽  
Richard B. Pearson ◽  
Anthony T. Papenfuss ◽  
David L. Goode
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Point Mutations ◽  
Primitive Elements ◽  
Clinical Value ◽  
Recurrent Point ◽  
Downstream Target ◽  
Transcriptional Alterations ◽  
Transcriptional Changes ◽  
Regulator Genes

AbstractExtensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumours, we show many transcriptional changes in tumours are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent point mutations were enriched in regulator genes linking unicellular and multicellular subnetworks, while copy-number alterations affected downstream target genes in distinctly unicellular and multicellular regions of the GRN. Our results depict drivers of tumourigenesis as genes that created key regulatory links during the evolution of early multicellular life, whose dysfunction creates widespread dysregulation of primitive elements of the GRN. Several genes we identified as important in this process were associated with drug response, demonstrating the potential clinical value of our approach.

scholarly journals Somatic mutations in early metazoan genes disrupt regulatory links between unicellular and multicellular genes in cancer

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Anna S Trigos ◽  
Richard B Pearson ◽  
Anthony T Papenfuss ◽  
David L Goode
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Point Mutations ◽  
Primitive Elements ◽  
Clinical Value ◽  
Recurrent Point ◽  
Downstream Target ◽  
Transcriptional Alterations ◽  
Transcriptional Changes ◽  
Regulator Genes

Extensive transcriptional alterations are observed in cancer, many of which activate core biological processes established in unicellular organisms or suppress differentiation pathways formed in metazoans. Through rigorous, integrative analysis of genomics data from a range of solid tumors, we show many transcriptional changes in tumors are tied to mutations disrupting regulatory interactions between unicellular and multicellular genes within human gene regulatory networks (GRNs). Recurrent point mutations were enriched in regulator genes linking unicellular and multicellular subnetworks, while copy-number alterations affected downstream target genes in distinctly unicellular and multicellular regions of the GRN. Our results depict drivers of tumourigenesis as genes that created key regulatory links during the evolution of early multicellular life, whose dysfunction creates widespread dysregulation of primitive elements of the GRN. Several genes we identified as important in this process were associated with drug response, demonstrating the potential clinical value of our approach.

scholarly journals The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Margaret E Torrence ◽  
Michael R MacArthur ◽  
Aaron M Hosios ◽  
Alexander J Valvezan ◽  
John M Asara ◽  
...  
Keyword(s):  
Target Genes ◽  
Human Cancer ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Glutathione Synthesis ◽  
Human Cancer Cell Lines ◽  
Downstream Target ◽  
Mtorc1 Signaling ◽  
Transcriptional Changes ◽  
Established Role

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast (MEF) and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

scholarly journals Commensal microbiota drive the functional diversification of colon macrophages

2019 ◽  
Vol 13 (2) ◽  
pp. 216-229 ◽  
Author(s):  
Byunghyun Kang ◽  
Luigi J. Alvarado ◽  
Teayong Kim ◽  
Michael L. Lehmann ◽  
Hyeseon Cho ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Target Genes ◽  
Myeloid Cell ◽  
Mononuclear Phagocytes ◽  
Developmental Pathways ◽  
Functional Diversification ◽  
Downstream Target ◽  
Commensal Microbiota ◽  
Specific Pathogen ◽  
Gene Regulatory

AbstractMononuclear phagocytes are a heterogeneous population of leukocytes essential for immune homeostasis that develop tissue-specific functions due to unique transcriptional programs driven by local microenvironmental cues. Single cell RNA sequencing (scRNA-seq) of colonic myeloid cells from specific pathogen free (SPF) and germ-free (GF) C57BL/6 mice revealed extensive heterogeneity of both colon macrophages (MPs) and dendritic cells (DCs). Modeling of developmental pathways combined with inference of gene regulatory networks indicate two major trajectories from common CCR2+ precursors resulting in colon MP populations with unique transcription factors and downstream target genes. Compared to SPF mice, GF mice had decreased numbers of total colon MPs, as well as selective proportional decreases of two major CD11c+CD206intCD121b+ and CD11c−CD206hiCD121b− colon MP populations, whereas DC numbers and proportions were not different. Importantly, these two major colon MP populations were clearly distinct from other colon MP populations regarding their gene expression profile, localization within the lamina propria (LP) and ability to phagocytose macromolecules from the blood. These data uncover the diversity of intestinal myeloid cell populations at the molecular level and highlight the importance of microbiota on the unique developmental as well as anatomical and functional fates of colon MPs.

scholarly journals The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

2020 ◽  
Author(s):  
Margaret E. Torrence ◽  
Michael R. MacArthur ◽  
Aaron M. Hosios ◽  
Alexander J. Valvezan ◽  
John M. Asara ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Target Genes ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Glutathione Synthesis ◽  
Downstream Target ◽  
Mechanistic Target Of Rapamycin ◽  
Transcriptional Changes ◽  
Growth Promoting ◽  
Established Role

AbstractThe mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the adaptive stress-responsive transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, how ATF4 functions in response to these distinct modes of regulation and its broader role as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon activation of mTORC1 or the ISR. The mTORC1-ATF4 pathway stimulated the expression of only a subset of the ATF4 target genes stimulated by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

scholarly journals Dynamics of genetic variation in Transcription Factors and its implications for the evolution of regulatory networks in Bacteria

2019 ◽  
Author(s):  
Farhan Ali ◽  
Aswin Sai Narain Seshasayee
Keyword(s):  
Genetic Variation ◽  
Transcription Factors ◽  
Regulatory Networks ◽  
Large Scale ◽  
Target Genes ◽  
Point Mutations ◽  
Purifying Selection ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Global Regulators

AbstractThe evolution of bacterial regulatory networks has largely been explained at macroevolutionary scales through lateral gene transfer and gene duplication. Transcription factors (TF) have been found to be less conserved across species than their target genes (TG). This would be expected if TFs accumulate mutations faster than TGs. This hypothesis is supported by several lab evolution studies which found TFs, especially global regulators, to be frequently mutated. Despite these studies, the contribution of point mutations in TFs to the evolution of regulatory network is poorly understood. We tested if TFs show greater genetic variation than their TGs using whole-genome sequencing data from a large collection of E coli isolates. We found TFs to be less diverse, across natural isolates, due to their regulatory roles. TFs were enriched in mutations in multiple adaptive lab evolution studies but not in mutation accumulation. However, over long-term evolution, relative frequency of mutations in TFs showed a gradual decay after a rapid initial burst. Our results suggest that point mutations, conferring large-scale expression changes, may drive the early stages of adaptation but gene regulation is subjected to stronger purifying selection post adaptation.

scholarly journals Epigenetic Associations between lncRNA/circRNA and miRNA in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2622 ◽  
Author(s):  
Tae-Su Han ◽  
Keun Hur ◽  
Hyun-Soo Cho ◽  
Hyun Seung Ban
Keyword(s):  
Hepatocellular Carcinoma ◽  
Regulatory Networks ◽  
Epithelial To Mesenchymal Transition ◽  
Target Genes ◽  
Circular Rnas ◽  
Cancer Cell Growth ◽  
Mesenchymal Transition ◽  
Downstream Target ◽  
Non Coding Rnas ◽  
Regulation Model

The three major members of non-coding RNAs (ncRNAs), named microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play an important role in hepatocellular carcinoma (HCC) development. Recently, the competing endogenous RNA (ceRNA) regulation model described lncRNA/circRNA as a sponge for miRNAs to indirectly regulate miRNA downstream target genes. Accumulating evidence has indicated that ceRNA regulatory networks are associated with biological processes in HCC, including cancer cell growth, epithelial to mesenchymal transition (EMT), metastasis, and chemoresistance. In this review, we summarize recent discoveries, which are specific ceRNA regulatory networks (lncRNA/circRNA-miRNA-mRNA) in HCC and discuss their clinical significance.

Combined physiological, transcriptome, and genetic analysis reveals a molecular network of nitrogen remobilization in maize

2020 ◽  
Vol 71 (16) ◽  
pp. 5061-5073
Author(s):  
Xiaoping Gong ◽  
Xiaoyang Liu ◽  
Qingchun Pan ◽  
Guohua Mi ◽  
Fanjun Chen ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Leaf Senescence ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Target Genes ◽  
Protease Gene ◽  
Nitrogen Remobilization ◽  
Downstream Target ◽  
Source To Sink ◽  
Trait Locus

Abstract In plants, nitrogen remobilization from source to sink organs is an important process regulated by complex transcriptional regulatory networks. However, the relationship between nitrogen remobilization and leaf senescence and the molecular regulatory network that controls them are unknown in maize. Here, using 15N labeling and a transcriptome approach, a dynamic analysis of the nitrogen remobilization process was conducted in two elite maize inbred lines (PH4CV and PH6WC) with contrasting leaf senescence. PH4CV showed higher nitrogen remobilization efficiency (NRE) than PH6WC, mainly in the middle and lower leaves from 15 d to 35 d after silking. The co-expression network analysis revealed that ethylene and cytokinin metabolism-related genes triggered the onset of nitrogen remobilization, while abscisic acid and jasmonic acid biosynthesis-related genes controlled the progression of nitrogen remobilization. By integrating genetic analysis, functional annotation, and gene expression, two candidate genes underlying a major quantitative trait locus of NRE were identified, namely an early senescence acting gene (ZmASR6) and an ATP-dependent Clp protease gene (GRMZM2G172230). Hormone-coupled transcription factors and downstream target genes reveal a gene regulatory network for the nitrogen remobilization process after silking in maize. These results uncovered a sophisticated regulatory mechanism for nitrogen remobilization, and further provided characterization of valuable genes for genetic improvement of nitrogen use efficiency in maize.

scholarly journals Dynamics of genetic variation in transcription factors and its implications for the evolution of regulatory networks in Bacteria

2020 ◽  
Vol 48 (8) ◽  
pp. 4100-4114
Author(s):  
Farhan Ali ◽  
Aswin Sai Narain Seshasayee
Keyword(s):  
Genetic Variation ◽  
Transcription Factors ◽  
Regulatory Networks ◽  
Large Scale ◽  
Mutation Frequency ◽  
Target Genes ◽  
Point Mutations ◽  
Whole Genome Sequencing Data ◽  
Laboratory Evolution

Abstract The evolution of regulatory networks in Bacteria has largely been explained at macroevolutionary scales through lateral gene transfer and gene duplication. Transcription factors (TF) have been found to be less conserved across species than their target genes (TG). This would be expected if TFs accumulate mutations faster than TGs. This hypothesis is supported by several lab evolution studies which found TFs, especially global regulators, to be frequently mutated. Despite these studies, the contribution of point mutations in TFs to the evolution of regulatory network is poorly understood. We tested if TFs show greater genetic variation than their TGs using whole-genome sequencing data from a large collection of Escherichia coli isolates. TFs were less diverse than their TGs across natural isolates, with TFs of large regulons being more conserved. In contrast, TFs showed higher mutation frequency in adaptive laboratory evolution experiments. However, over long-term laboratory evolution spanning 60 000 generations, mutation frequency in TFs gradually declined after a rapid initial burst. Extrapolating the dynamics of genetic variation from long-term laboratory evolution to natural populations, we propose that point mutations, conferring large-scale gene expression changes, may drive the early stages of adaptation but gene regulation is subjected to stronger purifying selection post adaptation.

scholarly journals Deep Sequencing of the Rat MCAO Cortexes Reveals Crucial circRNAs Involved in Early Stroke Events and Their Regulatory Networks

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Chengtan Wang ◽  
Yuying Yang ◽  
Mengsi Xu ◽  
Fuxiu Mao ◽  
Peng Yang ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Deep Sequencing ◽  
Posttranscriptional Regulation ◽  
Regulatory Networks ◽  
Target Genes ◽  
Interaction Network ◽  
Artery Occlusion ◽  
Circular Rnas ◽  
Sprague Dawley ◽  
Downstream Target

Circular RNAs (circRNAs) are highly enriched in the central nervous system and significantly involved in a range of brain-related physiological and pathological processes. Ischemic stroke is a complex disorder caused by multiple factors; however, whether brain-derived circRNAs participate in the complex regulatory networks involved in stroke pathogenesis remains unknown. Here, we successfully constructed a cerebral ischemia-injury model of middle cerebral artery occlusion (MCAO) in male Sprague-Dawley rats. Preliminary qualitative and quantitative analyses of poststroke cortical circRNAs were performed through deep sequencing, and RT-PCR and qRT-PCR were used for validation. Of the 24,858 circRNAs expressed in the rat cerebral cortex, 294 circRNAs were differentially expressed in the ipsilateral cerebral cortex between the MCAO and sham rat groups. Cluster, GO, and KEGG analyses showed enrichments of these circRNAs and their host genes in numerous biological processes and pathways closely related to stroke. We selected 106 of the 294 circRNAs and constructed a circRNA-miRNA-mRNA interaction network comprising 577 sponge miRNAs and 696 target mRNAs. In total, 15 key potential circRNAs were predicted to be involved in the posttranscriptional regulation of a series of downstream target genes, which are widely implicated in poststroke processes, such as oxidative stress, apoptosis, inflammatory response, and nerve regeneration, through the competing endogenous RNA mechanism. Thus, circRNAs appear to be involved in multilevel actions that regulate the vast network of multiple mechanisms and events that occur after a stroke. These results provide novel insights into the complex pathophysiological mechanisms of stroke.

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