scholarly journals In vitro gene regulatory networks predict in vivo function of liver

2010 ◽  
Vol 4 (1) ◽  
Author(s):  
Youping Deng ◽  
David R Johnson ◽  
Xin Guan ◽  
Choo Y Ang ◽  
Junmei Ai ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Gene Regulatory

scholarly journals The emerging landscape of in vitro and in vivo epigenetic allelic effects

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2108 ◽  
Author(s):  
Christopher Gregg
Keyword(s):  
Cell Fate ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Disease Susceptibility ◽  
Monoallelic Expression ◽  
Functional Studies ◽  
Cell Type Specific ◽  
Gene Regulatory

Epigenetic mechanisms that cause maternally and paternally inherited alleles to be expressed differently in offspring have the potential to radically change our understanding of the mechanisms that shape disease susceptibility, phenotypic variation, cell fate, and gene expression. However, the nature and prevalence of these effects in vivo have been unclear and are debated. Here, I consider major new studies of epigenetic allelic effects in cell lines and primary cells and in vivo. The emerging picture is that these effects take on diverse forms, and this review attempts to clarify the nature of the different forms that have been uncovered for genomic imprinting and random monoallelic expression (RME). I also discuss apparent discrepancies between in vitro and in vivo studies. Importantly, multiple studies suggest that allelic effects are prevalent and can be developmental stage- and cell type-specific. I propose some possible functions and consider roles for allelic effects within the broader context of gene regulatory networks, cellular diversity, and plasticity. Overall, the field is ripe for discovery and is in need of mechanistic and functional studies.

scholarly journals Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets

2016 ◽  
Vol 113 (13) ◽  
pp. E1835-E1843 ◽  
Author(s):  
Mina Fazlollahi ◽  
Ivor Muroff ◽  
Eunjee Lee ◽  
Helen C. Causton ◽  
Harmen J. Bussemaker
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Nonsynonymous Mutation ◽  
Gene Regulatory ◽  
Genetic Modulators

Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae. We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.

scholarly journals Mapping gene regulatory networks of primary CD4+T cells using single-cell genomics and genome engineering

2019 ◽  
Author(s):  
Rachel E. Gate ◽  
Min Cheol Kim ◽  
Andrew Lu ◽  
David Lee ◽  
Eric Shifrut ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Genome Engineering ◽  
Regulatory Elements ◽  
Mapping Gene ◽  
Gene Regulatory ◽  
Novel Interactions

AbstractGene regulatory programs controlling the activation and polarization of CD4+T cells are incompletely mapped and the interindividual variability in these programs remain unknown. We sequenced the transcriptomes of ~160k CD4+T cells from 9 donors following pooled CRISPR perturbation targeting 140 regulators. We identified 134 regulators that affect T cell functionalization, includingIRF2as a positive regulator of Th2polarization. Leveraging correlation patterns between cells, we mapped 194 pairs of interacting regulators, including known (e.g.BATFandJUN) and novel interactions (e.g.ETS1andSTAT6). Finally, we identified 80 natural genetic variants with effects on gene expression, 48 of which are modified by a perturbation. In CD4+T cells, CRISPR perturbations can influencein vitropolarization and modify the effects oftransandcisregulatory elements on gene expression.

scholarly journals Compensatory mutation can drive gene regulatory network evolution

2019 ◽  
Author(s):  
Yifei Wang ◽  
Marios Richards ◽  
Steve Dorus ◽  
Nicholas K. Priest ◽  
Joanna J. Bryson
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Network Evolution ◽  
Regulatory Function ◽  
Compensatory Mutation ◽  
Relaxed Selection ◽  
Mutation Site ◽  
Regulatory Pathways ◽  
Gene Regulatory

AbstractGene regulatory networks underlie every aspect of life; better understanding their assembly would better our understanding of evolution more generally. For example, evolutionary theory typically assumed that low-fitness intermediary pathways are not a significant factor in evolution, yet there is substantial empirical evidence of compensatory mutation. Here we revise theoretical assumptions to explore the possibility that compensatory mutation may drive rapid evolutionary recovery. Using a well-established in silico model of gene regulatory networks, we show that assuming only that deleterious mutations are not fatal, compensatory mutation is surprisingly frequent. Further, we find that it entails biases that drive the evolution of regulatory pathways. In our simulations, we find compensatory mutation to be common during periods of relaxed selection, with 8-15% of degraded networks having regulatory function restored by a single randomly-generated additional mutation. Though this process reduces average robustness, proportionally higher robustness is found in networks where compensatory mutations occur close to the deleterious mutation site, or where the compensatory mutation results in a large regulatory effect size. This location- and size-specific robustness systematically biases which networks are purged by selection for network stability, producing emergent changes to the population of regulatory networks. We show that over time, large-effect and co-located mutations accumulate, assuming only that episodes of relaxed selection occur, even very rarely. This accumulation results in an increase in regulatory complexity. Our findings help explain a process by which large-effect mutations structure complex regulatory networks, and may account for the speed and pervasiveness of observed occurrence of compensatory mutation, for example in the context of antibiotic resistance, which we discuss. If sustained by in vitro experiments, these results promise a significant breakthrough in the understanding of evolutionary and regulatory processes.

scholarly journals Nuclear Transfer Arrest Embryos Show Massive Dysregulation of Genes Involved in Transcription Pathways

2021 ◽  
Vol 22 (15) ◽  
pp. 8187
Author(s):  
Chunshen Long ◽  
Hanshuang Li ◽  
Xinru Li ◽  
Wuritu Yang ◽  
Yongchun Zuo
Keyword(s):  
Gene Regulatory Networks ◽  
Nuclear Transfer ◽  
Regulatory Networks ◽  
Target Genes ◽  
Epigenetic Modification ◽  
Cell Nuclei ◽  
Activation Of Transcription ◽  
Gene Regulatory ◽  
Catabolic Process

Somatic cell nuclear transfer (SCNT) technology can reprogram terminally differentiated cell nuclei into a totipotent state. However, the underlying molecular barriers of SCNT embryo development remain incompletely elucidated. Here, we observed that transcription-related pathways were incompletely activated in nuclear transfer arrest (NTA) embryos compared to normal SCNT embryos and in vivo fertilized (WT) embryos, which hinders the development of SCNT embryos. We further revealed the transcription pathway associated gene regulatory networks (GRNs) and found the aberrant transcription pathways can lead to the massive dysregulation of genes in NTA embryos. The predicted target genes of transcription pathways contain a series of crucial factors in WT embryos, which play an important role in catabolic process, pluripotency regulation, epigenetic modification and signal transduction. In NTA embryos, however, these genes were varying degrees of inhibition and show a defect in synergy. Overall, our research found that the incomplete activation of transcription pathways is another potential molecular barrier for SCNT embryos besides the incomplete reprogramming of epigenetic modifications, broadening the understanding of molecular mechanism of SCNT embryonic development.

scholarly journals Enhanced chromatin accessibility contributes to X chromosome dosage compensation in mammals

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Irene Talon ◽  
Adrian Janiszewski ◽  
Bart Theeuwes ◽  
Thomas Lefevre ◽  
Juan Song ◽  
...  
Keyword(s):  
X Chromosome ◽  
Gene Regulatory Networks ◽  
Mammalian Cells ◽  
Regulatory Networks ◽  
Gene Dosage ◽  
Somatic Cells ◽  
Chromatin Accessibility ◽  
Chromosome Loss ◽  
Gene Regulatory

Abstract Background Precise gene dosage of the X chromosomes is critical for normal development and cellular function. In mice, XX female somatic cells show transcriptional X chromosome upregulation of their single active X chromosome, while the other X chromosome is inactive. Moreover, the inactive X chromosome is reactivated during development in the inner cell mass and in germ cells through X chromosome reactivation, which can be studied in vitro by reprogramming of somatic cells to pluripotency. How chromatin processes and gene regulatory networks evolved to regulate X chromosome dosage in the somatic state and during X chromosome reactivation remains unclear. Results Using genome-wide approaches, allele-specific ATAC-seq and single-cell RNA-seq, in female embryonic fibroblasts and during reprogramming to pluripotency, we show that chromatin accessibility on the upregulated mammalian active X chromosome is increased compared to autosomes. We further show that increased accessibility on the active X chromosome is erased by reprogramming, accompanied by erasure of transcriptional X chromosome upregulation and the loss of increased transcriptional burst frequency. In addition, we characterize gene regulatory networks during reprogramming and X chromosome reactivation, revealing changes in regulatory states. Our data show that ZFP42/REX1, a pluripotency-associated gene that evolved specifically in placental mammals, targets multiple X-linked genes, suggesting an evolutionary link between ZFP42/REX1, X chromosome reactivation, and pluripotency. Conclusions Our data reveal the existence of intrinsic compensatory mechanisms that involve modulation of chromatin accessibility to counteract X-to-Autosome gene dosage imbalances caused by evolutionary or in vitro X chromosome loss and X chromosome inactivation in mammalian cells.

scholarly journals Gene regulatory networks controlled by FLOWERING LOCUS C that confer variation in seasonal flowering and life history

2020 ◽  
Author(s):  
Eva Madrid ◽  
John W Chandler ◽  
George Coupland
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Higher Plants ◽  
Floral Transition ◽  
Environmental Cues ◽  
Flowering Locus C ◽  
Gene Regulatory ◽  
Flowering Locus

Abstract Responses to environmental cues synchronize reproduction of higher plants to the changing seasons. The genetic basis of these responses has been intensively studied in the Brassicaceae. The MADS-domain transcription factor FLOWERING LOCUS C (FLC) plays a central role in the regulatory network that controls flowering of Arabidopsis thaliana in response to seasonal cues. FLC blocks flowering until its transcription is stably repressed by extended exposure to low temperatures in autumn or winter and, therefore, FLC activity is assumed to limit flowering to spring. Recent reviews describe the complex epigenetic mechanisms responsible for FLC repression in cold. We focus on the gene regulatory networks controlled by FLC and how they influence floral transition. Genome-wide approaches determined the in vivo target genes of FLC and identified those whose transcription changes during vernalization or in flc mutants. We describe how studying FLC targets such as FLOWERING LOCUS T, SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 15, and TARGET OF FLC AND SVP 1 can explain different flowering behaviours in response to vernalization and other environmental cues, and help define mechanisms by which FLC represses gene transcription. Elucidating the gene regulatory networks controlled by FLC provides access to the developmental and physiological mechanisms that regulate floral transition.

scholarly journals DET1-mediated COP1 regulation avoids HY5 activity over second-site targets to tune plant photomorphogenesis

2020 ◽  
Author(s):  
Esther Cañibano ◽  
Clara Bourbousse ◽  
Marta Garcia-Leon ◽  
Lea Wolff ◽  
Camila Garcia-Baudino ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Negative Regulator ◽  
Protein Abundance ◽  
Mass Spectrometry Identification ◽  
Associated Proteins ◽  
Gene Regulatory

AbstractDE-ETIOLATED1 (DET1) is a negative regulator of plant photomorphogenesis acting as a component of the C3D complex, which can further associate to CULLIN4 to form a CRL4C3D E3 ubiquitin ligase. CRL4C3D is thought to act together with CRL4COP1SPA ubiquitin ligase, to promote the ubiquitin-mediated degradation of the master regulatory transcription factor ELONGATED HYPOCOTYL5 (HY5), thereby controlling photomorphogenic gene regulatory networks. Yet, functional links between COP1 and DET1 have long remained elusive. Here, upon mass spectrometry identification of DET1 and COP1-associated proteins, we provide in vivo evidence that DET1 associates with COP1 to promote its destabilization, a process necessary to dampen HY5 protein abundance. By regulating HY5 over-accumulation, DET1 is critical to avoid its association to second-site loci, including many PIF3 target genes. Accordingly, excessive HY5 levels result in an increased HY5 repressive activity and are sufficient to trigger fusca-like phenotypes otherwise observed typically in COP1 and COP9 signalosome mutant seedlings. This study therefore identifies that DET1-mediated regulation of COP1 stability tunes down HY5 cistrome and avoids hyper-photomorphogenic responses that might compromise plant viability.

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