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 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 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 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 A primate-specific retroviral enhancer wires the XACT lncRNA into the core pluripotency network in humans

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Miguel Casanova ◽  
Madeleine Moscatelli ◽  
Louis Édouard Chauvière ◽  
Christophe Huret ◽  
Julia Samson ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Endogenous Retroviruses ◽  
X Chromosomes ◽  
Regulatory Pathways ◽  
Gene Regulatory ◽  
Non Coding Rnas ◽  
Specific Regulation ◽  
Species Specific ◽  
And Function

AbstractTransposable elements (TEs) have been proposed to play an important role in driving the expansion of gene regulatory networks during mammalian evolution, notably by contributing to the evolution and function of long non-coding RNAs (lncRNAs). XACT is a primate-specific TE-derived lncRNA that coats active X chromosomes in pluripotent cells and may contribute to species-specific regulation of X-chromosome inactivation. Here we explore how different families of TEs have contributed to shaping the XACT locus and coupling its expression to pluripotency. Through a combination of sequence analysis across primates, transcriptional interference, and genome editing, we identify a critical enhancer for the regulation of the XACT locus that evolved from an ancestral group of mammalian endogenous retroviruses (ERVs), prior to the emergence of XACT. This ERV was hijacked by younger hominoid-specific ERVs that gave rise to the promoter of XACT, thus wiring its expression to the pluripotency network. This work illustrates how retroviral-derived sequences may intervene in species-specific regulatory pathways.

scholarly journals Phase transitions and assortativity in models of gene regulatory networks evolved under different selection processes

2021 ◽  
Vol 18 (177) ◽  
Author(s):  
Brandon Alexander ◽  
Alexandra Pushkar ◽  
Michelle Girvan
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Large Scale ◽  
Target Genes ◽  
Network Evolution ◽  
Network Nodes ◽  
Individual Gene ◽  
Damage Propagation ◽  
Selection Processes ◽  
Gene Regulatory

We study a simplified model of gene regulatory network evolution in which links (regulatory interactions) are added via various selection rules that are based on the structural and dynamical features of the network nodes (genes). Similar to well-studied models of ‘explosive’ percolation, in our approach, links are selectively added so as to delay the transition to large-scale damage propagation, i.e. to make the network robust to small perturbations of gene states. We find that when selection depends only on structure, evolved networks are resistant to widespread damage propagation, even without knowledge of individual gene propensities for becoming ‘damaged’. We also observe that networks evolved to avoid damage propagation tend towards disassortativity (i.e. directed links preferentially connect high degree ‘source’ genes to low degree ‘target’ genes and vice versa). We compare our simulations to reconstructed gene regulatory networks for several different species, with genes and links added over evolutionary time, and we find a similar bias towards disassortativity in the reconstructed networks.

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 Identifying genes and regulatory pathways associated with the scleractinian coral calcification process

PeerJ ◽  
2017 ◽  
Vol 5 ◽  
pp. e3590 ◽  
Author(s):  
Eldad Gutner-Hoch ◽  
Hiba Waldman Ben-Asher ◽  
Ruth Yam ◽  
Aldo Shemesh ◽  
Oren Levy
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Stylophora Pistillata ◽  
Regulatory Pathways ◽  
Animal Body ◽  
High Calcium ◽  
Gene Regulatory ◽  
Calcification Process

Reef building corals precipitate calcium carbonate as an exo-skeleton and provide substratum for prosperous marine life. Biomineralization of the coral’s skeleton is a developmental process that occurs concurrently with other proliferation processes that control the animal extension and growth. The development of the animal body is regulated by large gene regulatory networks, which control the expression of gene sets that progressively generate developmental patterns in the animal body. In this study we have explored the gene expression profile and signaling pathways followed by the calcification process of a basal metazoan, the Red Sea scleractinian (stony) coral,Stylophora pistillata. When treated by seawater with high calcium concentrations (addition of 100 gm/L, added as CaCl2.2H2O), the coral increases its calcification rates and associated genes were up-regulated as a result, which were then identified. Gene expression was compared between corals treated with elevated and normal calcium concentrations. Calcification rate measurements and gene expression analysis by microarray RNA transcriptional profiling at two time-points (midday and night-time) revealed several genes common within mammalian gene regulatory networks. This study indicates that core genes of the Wnt and TGF-β/BMP signaling pathways may also play roles in development, growth, and biomineralization in early-diverging organisms such as corals.

scholarly journals Master regulators of skeletal muscle lineage development and pluripotent stem cells differentiation

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Joana Esteves de Lima ◽  
Frédéric Relaix
Keyword(s):  
Stem Cells ◽  
Gene Regulatory Networks ◽  
Pluripotent Stem Cells ◽  
Regulatory Networks ◽  
Myogenic Differentiation ◽  
Muscle Growth ◽  
The Body ◽  
Gene Regulatory ◽  
Cell Commitment

AbstractIn vertebrates, the skeletal muscles of the body and their associated stem cells originate from muscle progenitor cells, during development. The specification of the muscles of the trunk, head and limbs, relies on the activity of distinct genetic hierarchies. The major regulators of trunk and limb muscle specification are the paired-homeobox transcription factors PAX3 and PAX7. Distinct gene regulatory networks drive the formation of the different muscles of the head. Despite the redeployment of diverse upstream regulators of muscle progenitor differentiation, the commitment towards the myogenic fate requires the expression of the early myogenic regulatory factors MYF5, MRF4, MYOD and the late differentiation marker MYOG. The expression of these genes is activated by muscle progenitors throughout development, in several waves of myogenic differentiation, constituting the embryonic, fetal and postnatal phases of muscle growth. In order to achieve myogenic cell commitment while maintaining an undifferentiated pool of muscle progenitors, several signaling pathways regulate the switch between proliferation and differentiation of myoblasts. The identification of the gene regulatory networks operating during myogenesis is crucial for the development of in vitro protocols to differentiate pluripotent stem cells into myoblasts required for regenerative medicine.

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