Rewiring Of Regulatory Networks Research Articles

Network-based prioritization and validation of regulators of vascular smooth muscle cell proliferation in disease

Aberrant vascular smooth muscle cell (VSMC) homeostasis and proliferation characterize vascular diseases causing heart attack and stroke. Here we elucidate molecular determinants governing VSMC proliferation by reconstructing gene regulatory networks from single-cell transcriptomics and epigenetic profiling. We detect widespread activation of enhancers at disease-relevant loci in proliferation-predisposed VSMCs. We compared gene regulatory network rewiring between injury-responsive and nonresponsive VSMCs, which suggested shared transcription factors but differing target loci between VSMC states. Through in silico perturbation analysis, we identified and prioritized previously unrecognized regulators of proliferation, including RUNX1 and TIMP1. Moreover, we showed that the pioneer transcription factor RUNX1 increased VSMC responsiveness and that TIMP1 feeds back to promote VSMC proliferation through CD74-mediated STAT3 signaling. Both RUNX1 and the TIMP1–CD74 axis were expressed in human VSMCs, showing low levels in normal arteries and increased expression in disease, suggesting clinical relevance and potential as vascular disease targets.

Transcription factor expression levels and environmental signals constrain transcription factor innovation.

Evolutionary innovation of transcription factors frequently drives phenotypic diversification and adaptation to environmental change. Transcription factors can gain or lose connections to target genes, resulting in novel regulatory responses and phenotypes. However the frequency of functional adaptation varies between different regulators, even when they are closely related. To identify factors influencing propensity for innovation, we utilise a Pseudomonas fluorescens SBW25 strain rendered incapable of flagellar mediated motility in soft-agar plates via deletion of the flagellar master regulator (fleQ). This bacterium can evolve to rescue flagellar motility via gene regulatory network rewiring of an alternative transcription factor to rescue activity of FleQ. Previously, we have identified two members (out of 22) of the RpoN-dependent enhancer binding protein (RpoN-EBP) family of transcription factors (NtrC and PFLU1132) that are capable of innovating in this way. These two transcription factors rescue motility repeatably and reliably in a strict hierarchy – with NtrC the only route in a ∆fleQ background, and PFLU1132 the only route in a ∆fleQ∆ntrC background. However, why other members in the same transcription factor family have not been observed to rescue flagellar activity is unclear. Previous work shows that protein homology cannot explain this pattern within the protein family (RpoN-EBPs), and mutations in strains that rescued motility suggested high levels of transcription factor expression and activation drive innovation. We predict that mutations that increase expression of the transcription factor are vital to unlock evolutionary potential for innovation. Here, we construct titratable expression mutant lines for 11 of the RpoN-EBPs in P. fluorescens . We show that in five additional RpoN-EBPs (FleR, HbcR, GcsR, DctD, AauR and PFLU2209), high expression levels result in different mutations conferring motility rescue, suggesting alternative rewiring pathways. Our results indicate that expression levels (and not protein homology) of RpoN-EBPs are a key constraining factor in determining evolutionary potential for innovation. This suggests that transcription factors that can achieve high expression through few mutational changes, or transcription factors that are active in the selective environment, are more likely to innovate and contribute to adaptive gene regulatory network evolution.

Genomic innovation and regulatory rewiring during evolution of the cotton genus Gossypium.

Phenotypic diversity and evolutionary innovation ultimately trace to variation in genomic sequence and rewiring of regulatory networks. Here, we constructed a pan-genome of the Gossypium genus using ten representative diploid genomes. We document the genomic evolutionary history and the impact of lineage-specific transposon amplification on differential genome composition. The pan-3D genome reveals evolutionary connections between transposon-driven genome size variation and both higher-order chromatin structure reorganization and the rewiring of chromatin interactome. We linked changes in chromatin structures to phenotypic differences in cotton fiber and identified regulatory variations that decode the genetic basis of fiber length, the latter enabled by sequencing 1,005 transcriptomes during fiber development. We showcase how pan-genomic, pan-3D genomic and genetic regulatory data serve as a resource for delineating the evolutionary basis of spinnable cotton fiber. Our work provides insights into the evolution of genome organization and regulation and will inform cotton improvement by enabling regulome-based approaches.

To stripe or not to stripe: the origin of a novel foliar pigmentation pattern in monkeyflowers (Mimulus).

The origin of phenotypic novelty is one of the most challenging problems in evolutionary biology. Although genetic regulatory network rewiring or co-option has been widely recognised as a major contributor, in most cases how such genetic rewiring/co-option happens is completely unknown. We have studied a novel foliar pigmentation pattern that evolved recently in the monkeyflower species Mimulus verbenaceus. Through genome-wide association tests using wild-collected samples, experimental crosses of laboratory inbred lines, gene expression analyses, and functional assays, we identified an anthocyanin-activating R2R3-MYB gene, STRIPY, as the causal gene triggering the emergence of the discrete, mediolateral anthocyanin stripe in the M. verbenaceus leaf. Chemical mutagenesis revealed the existence of upstream activators and repressors that form a 'hidden' prepattern along the leaf proximodistal axis, potentiating the unique expression pattern of STRIPY. Population genomics analyses did not reveal signatures of positive selection, indicating that nonadaptive processes may be responsible for the establishment of this novel trait in the wild. This study demonstrates that the origin of phenotypic novelty requires at least two separate phases, potentiation and actualisation. The foliar stripe pattern of M. verbenaceus provides an excellent platform to probe the molecular details of both processes in future studies.

Polyploidy and Myc Proto-Oncogenes Promote Stress Adaptation via Epigenetic Plasticity and Gene Regulatory Network Rewiring.

Polyploid cells demonstrate biological plasticity and stress adaptation in evolution; development; and pathologies, including cardiovascular diseases, neurodegeneration, and cancer. The nature of ploidy-related advantages is still not completely understood. Here, we summarize the literature on molecular mechanisms underlying ploidy-related adaptive features. Polyploidy can regulate gene expression via chromatin opening, reawakening ancient evolutionary programs of embryonality. Chromatin opening switches on genes with bivalent chromatin domains that promote adaptation via rapid induction in response to signals of stress or morphogenesis. Therefore, stress-associated polyploidy can activate Myc proto-oncogenes, which further promote chromatin opening. Moreover, Myc proto-oncogenes can trigger polyploidization de novo and accelerate genome accumulation in already polyploid cells. As a result of these cooperative effects, polyploidy can increase the ability of cells to search for adaptive states of cellular programs through gene regulatory network rewiring. This ability is manifested in epigenetic plasticity associated with traits of stemness, unicellularity, flexible energy metabolism, and a complex system of DNA damage protection, combining primitive error-prone unicellular repair pathways, advanced error-free multicellular repair pathways, and DNA damage-buffering ability. These three features can be considered important components of the increased adaptability of polyploid cells. The evidence presented here contribute to the understanding of the nature of stress resistance associated with ploidy and may be useful in the development of new methods for the prevention and treatment of cardiovascular and oncological diseases.

A single-cell map of dynamic chromatin landscapes of immune cells in renal cell carcinoma

A complete chart of the chromatin regulatory elements of immune cells in patients with cancer and their dynamic behavior is necessary to understand the developmental fates and guide therapeutic strategies. Here, we map the single-cell chromatin landscape of immune cells from blood, normal tumor-adjacent kidney tissue and malignant tissue from patients with early-stage clear cell renal cell carcinoma (ccRCC). We catalog the T cell states dictated by tissue-specific and developmental-stage-specific chromatin accessibility patterns, infer key chromatin regulators and observe rewiring of regulatory networks in the progression to dysfunction in CD8+ T cells. Unexpectedly, among the transcription factors orchestrating the path to dysfunction, NF-κB is associated with a pro-apoptotic program in late stages of dysfunction in tumor-infiltrating CD8+ T cells. Importantly, this epigenomic profiling stratified ccRCC patients based on a NF-κB-driven pro-apoptotic signature. This study provides a rich resource for understanding the functional states and regulatory dynamics of immune cells in ccRCC.

Evolutionary rewiring of regulatory networks contributes to phenotypic differences between human and mouse orthologous genes.

Mouse models have been engineered to reveal the biological mechanisms of human diseases based on an assumption. The assumption is that orthologous genes underlie conserved phenotypes across species. However, genetically modified mouse orthologs of human genes do not often recapitulate human disease phenotypes which might be due to the molecular evolution of phenotypic differences across species from the time of the last common ancestor. Here, we systematically investigated the evolutionary divergence of regulatory relationships between transcription factors (TFs) and target genes in functional modules, and found that the rewiring of gene regulatory networks (GRNs) contributes to the phenotypic discrepancies that occur between humans and mice. We confirmed that the rewired regulatory networks of orthologous genes contain a higher proportion of species-specific regulatory elements. Additionally, we verified that the divergence of target gene expression levels, which was triggered by network rewiring, could lead to phenotypic differences. Taken together, a careful consideration of evolutionary divergence in regulatory networks could be a novel strategy to understand the failure or success of mouse models to mimic human diseases. To help interpret mouse phenotypes in human disease studies, we provide quantitative comparisons of gene expression profiles on our website (http://sbi.postech.ac.kr/w/RN).

3053 – DEFINING THE GENE REGULATORY NETWORKS TARGETED BY RUNX1 AND FLT3 INHIBITORS

FLT3-ITD is a common activating receptor mutation in AML. We used genome-wide profiling to show that genes upregulated in FLT3-ITD+ AML had open chromatin regions (DHSs) enriched in binding sites for AP-1 and RUNX1 (1), within a gene regulatory network downstream of MAPK. We showed that MAPK inhibitors (i) suppress genes upregulated by FLT3-ITD, and (ii) inhibit growth of FLT3-ITD+ cells. Furthermore, concurrent RUNX1 mutations result in a suppression of genes normally activated by FLT3-ITD. We compared responses to two inhibitors targeting the FLT3-ITD gene regulatory network: (1)Gilteritinib (FLT3i) which targets FLT3-ITD, and (2)AI-14-91 (CBFbi) which blocks interactions between RUNX1 and CBFb (2). Overall, the responses to the 2 inhibitors were similar, suggesting that AP-1 and RUNX1 are in the same pathway. Treatment of FLT3-ITD+ AML cells with CBFbi or FLT3i led to a modest reduction in intensity of a subset of DHSs enriched in AP-1 and RUNX1 motifs. However, many pre-existing DHSs not normally bound by AP-1 acquired binding of FOS, at genes upregulated after either treatment. CBFbi suppressed FLT3-ITD AML cell cultures, but not healthy CD34+ blood stem cells, or AML cells with mutated RUNX1, suggesting that CBFbi plus FLT3i could form an AML therapy. To investigate CBFbi further, we performed cell culture assays on AML cells from a FLT3-ITD+ AML patient on AC220 FLT3 inhibitor therapy, who relapsed with a FLT3 D835H mutation. AML cells from this patient remained sensitive to culture in CBFbi, suggesting that CBFbi and MAPK inhibitors might form a second line of therapy in FLT3-ITD AML. (1)Assi et al. Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nat Genet 51, 151-162 (2019). (2)Illendula et al. Small Molecule Inhibitor of CBFbeta-RUNX Binding for RUNX Transcription Factor Driven Cancers. EBioMedicine 8, 117-131 (2016). FLT3-ITD is a common activating receptor mutation in AML. We used genome-wide profiling to show that genes upregulated in FLT3-ITD+ AML had open chromatin regions (DHSs) enriched in binding sites for AP-1 and RUNX1 (1), within a gene regulatory network downstream of MAPK. We showed that MAPK inhibitors (i) suppress genes upregulated by FLT3-ITD, and (ii) inhibit growth of FLT3-ITD+ cells. Furthermore, concurrent RUNX1 mutations result in a suppression of genes normally activated by FLT3-ITD. We compared responses to two inhibitors targeting the FLT3-ITD gene regulatory network: (1)Gilteritinib (FLT3i) which targets FLT3-ITD, and (2)AI-14-91 (CBFbi) which blocks interactions between RUNX1 and CBFb (2). Overall, the responses to the 2 inhibitors were similar, suggesting that AP-1 and RUNX1 are in the same pathway. Treatment of FLT3-ITD+ AML cells with CBFbi or FLT3i led to a modest reduction in intensity of a subset of DHSs enriched in AP-1 and RUNX1 motifs. However, many pre-existing DHSs not normally bound by AP-1 acquired binding of FOS, at genes upregulated after either treatment. CBFbi suppressed FLT3-ITD AML cell cultures, but not healthy CD34+ blood stem cells, or AML cells with mutated RUNX1, suggesting that CBFbi plus FLT3i could form an AML therapy. To investigate CBFbi further, we performed cell culture assays on AML cells from a FLT3-ITD+ AML patient on AC220 FLT3 inhibitor therapy, who relapsed with a FLT3 D835H mutation. AML cells from this patient remained sensitive to culture in CBFbi, suggesting that CBFbi and MAPK inhibitors might form a second line of therapy in FLT3-ITD AML. (1)Assi et al. Subtype-specific regulatory network rewiring in acute myeloid leukemia. Nat Genet 51, 151-162 (2019). (2)Illendula et al. Small Molecule Inhibitor of CBFbeta-RUNX Binding for RUNX Transcription Factor Driven Cancers. EBioMedicine 8, 117-131 (2016).

Identifying biomarkers for breast cancer by gene regulatory network rewiring

BackgroundMining gene regulatory network (GRN) is an important avenue for addressing cancer mechanism. Mutations in cancer genome perturb GRN and cause a rewiring in an orchestrated network. Hence, the exploration of gene regulatory network rewiring is significant to discover potential biomarkers and indicators for discriminating cancer phenotypes.ResultsHere, we propose a new bioinformatics method of identifying biomarkers based on network rewiring in different states. It firstly reconstructs GRN in different phenotypic conditions from gene expression data with a priori background network. We employ the algorithm based on path consistency algorithm and conditional mutual information to delete false-positive regulatory interactions between independent nodes/genes or not closely related gene pairs. And then a differential gene regulatory network (D-GRN) is constructed from the rewiring parts in the two phenotype-specific GRNs. Community detection technique is then applied for D-GRN to detect functional modules. Finally, we apply logistic regression classifier with recursive feature elimination to select biomarker genes in each module individually. The extracted feature genes result in a gene set of biomarkers with impressing ability to distinguish normal samples from controls. We verify the identified biomarkers in external independent validation datasets. For a proof-of-concept study, we apply the framework to identify diagnostic biomarkers of breast cancer. The identified biomarkers obtain a maximum AUC of 0.985 in the internal sample classification experiments. And these biomarkers achieve a maximum AUC of 0.989 in the external validations.ConclusionIn conclusion, network rewiring reveals significant differences between different phenotypes, which indicating cancer dysfunctional mechanisms. With the development of sequencing technology, the amount and quality of gene expression data become available. Condition-specific gene regulatory networks that are close to the real regulations in different states will be established. Revealing the network rewiring will greatly benefit the discovery of biomarkers or signatures for phenotypes. D-GRN is a general method to meet this demand of deciphering the high-throughput data for biomarker discovery. It is also easy to be extended for identifying biomarkers of other complex diseases beyond breast cancer.

Mi-IsoNet: systems-scale microRNA landscape reveals rampant isoform-mediated gain of target interaction diversity and signaling specificity.

MicroRNA (miRNA) is not a single sequence, but a series of multiple variants (also termed isomiRs) with sequence and expression heterogeneity. Whether and how these isoforms contribute to functional variation and complexity at the systems and network levels remain largely unknown. To explore this question systematically, we comprehensively analyzed the expression of small RNAs and their target sites to interrogate functional variations between novel isomiRs and their canonical miRNA sequences. Our analyses of the pan-cancer landscape of miRNA expression indicate that multiple isomiRs generated from the same miRNA locus often exhibit remarkable variation in their sequence, expression and function. We interrogated abundant and differentially expressed 5' isomiRs with novel seed sequences via seed shifting and identified many potential novel targets of these 5' isomiRs that would expand interaction capabilities between small RNAs and mRNAs, rewiring regulatory networks and increasing signaling circuit complexity. Further analyses revealed that some miRNA loci might generate diverse dominant isomiRs that often involved isomiRs with varied seeds and arm-switching, suggesting a selective advantage of multiple isomiRs in regulating gene expression. Finally, experimental validation indicated that isomiRs with shifted seed sequences could regulate novel target mRNAs and therefore contribute to regulatory network rewiring. Our analysis uncovers a widespread expansion of isomiR and mRNA interaction networks compared with those seen in canonical small RNA analysis; this expansion suggests global gene regulation network perturbations by alternative small RNA variants or isoforms. Taken together, the variations in isomiRs that occur during miRNA processing and maturation are likely to play a far more complex and plastic role in gene regulation than previously anticipated.

Abstract 2478: Assessing regulatory network rewiring in cancer patients using chromatin accessibility profiles

Abstract The regulation of gene expression in humans is the result of a complex interplay between DNA, small RNA molecules and a multitude of proteins, particularly histones and transcription factors (TFs). To identify the key TFs regulating gene expression in cancer we are integrating ATAC-Seq data from 371 TCGA patients in conjunction with matching expression data and DNA-binding motifs for 780 TFs and TF families. We infer the regulatory networks in these patients by detecting true TF binding events in individual patients and the regulatory elements that said TFs are bound to using the Protein Interaction Quantification algorithm (PIQ). The inferred networks were then clustered by the similarity of inferred TF binding activity followed by identification of the TFs most likely driving the identity of each cluster. We observe robust clustering by site of origin of disease with canonical TFs such as FOXA1 and ESR1 being putative key TFs in ER+ breast cancer, PAX8 in renal cancer as well as TP63 and SOX2 in multiple squamous cell cancers. To validate these putative super-TFs, we used gene essentiality data from CRISPR-mediated knockout experiments of 18K genes in 625 well characterized cell lines performed by the Broad Institute. We observe statistically significant differences in the essentiality of putative super-TFs in cell lines matching the disease types of clusters. Citation Format: Andre Forbes, Duo Xu, Ekta K. Khurana. Assessing regulatory network rewiring in cancer patients using chromatin accessibility profiles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2478.

Prostate cancer risk SNP rs10993994 is a trans-eQTL for SNHG11 mediated through MSMB.

How genome-wide association studies-identified single-nucleotide polymorphisms (SNPs) affect remote genes remains unknown. Expression quantitative trait locus (eQTL) association meta-analysis on 496 prostate tumor and 602 normal prostate samples with 117 SNPs revealed novel cis-eQTLs and trans-eQTLs. Mediation testing and colocalization analysis demonstrate that MSMB is a cis-acting mediator for SNHG11 (P < 0.01). Removing rs10993994 in LNCaP cell lines by CRISPR/Cas9 editing shows that the C-allele corresponds with an over 100-fold increase in MSMB expression and 5-fold increase in SNHG11 compared with the T-allele. Colocalization analysis confirmed that the same set of SNPs associated with MSMB expression is associated with SNHG11 expression (posterior probability of shared variants is 66.6% in tumor and 91.4% in benign). These analyses further demonstrate variants driving MSMB expression differ in tumor and normal, suggesting regulatory network rewiring during tumorigenesis.

Transposable elements as genetic accelerators of evolution: contribution to genome size, gene regulatory network rewiring and morphological innovation

In the current era, as a growing number of genome sequence assemblies have been reported in animals, an in-depth analysis of transposable elements (TEs) is one of the most fundamental and essential studies for evolutionary genomics. Although TEs have, in general, been regarded as non-functional junk/selfish DNA, parasitic elements or harmful mutagens, studies have revealed that TEs have had a substantial and sometimes beneficial impact on host genomes in several ways. First, TEs are themselves diverse and thus provide lineage-specific characteristics to the genomes. Second, because TEs constitute a substantial fraction of animal genomes, they are a major contributing factor to evolutionary changes in genome size and composition. Third, host organisms have co-opted many repetitive sequences as genes, cis-regulatory elements and chromatin domain boundaries, which alter gene regulatory networks and in addition are partly involved in morphological evolution, as has been well documented in mammals. Here, I review the impact of TEs on various aspects of the genome, such as genome size and diversity in animals, as well as the evolution of gene networks and genome architecture in mammals. Given that a number of TE families probably remain to be discovered in many non-model organisms, unknown TEs may have contributed to gene networks in a much wider variety of animals than considered previously.

The Role of Gene Conversion between Transposable Elements in Rewiring Regulatory Networks.

Nature has found many ways to utilize transposable elements (TEs) throughout evolution. Many molecular and cellular processes depend on DNA-binding proteins recognizing hundreds or thousands of similar DNA motifs dispersed throughout the genome that are often provided by TEs. It has been suggested that TEs play an important role in the evolution of such systems, in particular, the rewiring of gene regulatory networks. One mechanism that can further enhance the rewiring of regulatory networks is nonallelic gene conversion between copies of TEs. Here, we will first review evidence for nonallelic gene conversion in TEs. Then, we will illustrate the benefits nonallelic gene conversion provides in rewiring regulatory networks. For instance, nonallelic gene conversion between TE copies offers an alternative mechanism to spread beneficial mutations that improve the network, it allows multiple mutations to be combined and transferred together, and it allows natural selection to work efficiently in spreading beneficial mutations and removing disadvantageous mutations. Future studies examining the role of nonallelic gene conversion in the evolution of TEs should help us to better understand how TEs have contributed to evolution.

Subtype-specific regulatory network rewiring in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease caused by a variety of mutations in transcription factors, epigenetic regulators and signaling molecules. To determine how different mutant regulators establish AML subtype-specific transcriptional networks we performed a comprehensive global analysis of cis-regulatory element activity and interaction, transcription factor occupancy and gene expression patterns in purified leukemic blast cells. Here, we focussed on specific sub-groups of patients carrying mutations in genes encoding transcription factors (RUNX1, CEBPA) and signaling molecules (FTL3-ITD, RAS, NPM1). Integrated analyses of these data demonstrates that each mutant regulator establishes a specific transcriptional and signaling network unrelated to that seen in normal cells, sustaining the expression of unique sets of genes required for AML growth and maintenance.

2025 - Subtype-specific regulatory network rewiring in acute myeloid leukemia

2025 - Subtype-specific regulatory network rewiring in acute myeloid leukemia

A Framework for Engineering Stress Resilient Plants Using Genetic Feedback Control and Regulatory Network Rewiring.

Crop disease leads to significant waste worldwide, both pre- and postharvest, with subsequent economic and sustainability consequences. Disease outcome is determined both by the plants' response to the pathogen and by the ability of the pathogen to suppress defense responses and manipulate the plant to enhance colonization. The defense response of a plant is characterized by significant transcriptional reprogramming mediated by underlying gene regulatory networks, and components of these networks are often targeted by attacking pathogens. Here, using gene expression data from Botrytis cinerea-infected Arabidopsis plants, we develop a systematic approach for mitigating the effects of pathogen-induced network perturbations, using the tools of synthetic biology. We employ network inference and system identification techniques to build an accurate model of an Arabidopsis defense subnetwork that contains key genes determining susceptibility of the plant to the pathogen attack. Once validated against time-series data, we use this model to design and test perturbation mitigation strategies based on the use of genetic feedback control. We show how a synthetic feedback controller can be designed to attenuate the effect of external perturbations on the transcription factor CHE in our subnetwork. We investigate and compare two approaches for implementing such a controller biologically-direct implementation of the genetic feedback controller, and rewiring the regulatory regions of multiple genes-to achieve the network motif required to implement the controller. Our results highlight the potential of combining feedback control theory with synthetic biology for engineering plants with enhanced resilience to environmental stress.

Developmental transcriptomics of the brittle star Amphiura filiformis reveals gene regulatory network rewiring in echinoderm larval skeleton evolution

BackgroundAmongst the echinoderms the class Ophiuroidea is of particular interest for its phylogenetic position, ecological importance and developmental and regenerative biology. However, compared to other echinoderms, notably echinoids (sea urchins), relatively little is known about developmental changes in gene expression in ophiuroids. To address this issue, we have generated and assembled a large RNAseq data set of four key stages of development in the brittle star Amphiura filiformis and a de novo reference transcriptome of comparable quality to that of a model echinoderm—the sea urchin Strongylocentrotus purpuratus. Furthermore, we provide access to the new data via a web interface: http://www.echinonet.eu/shiny/Amphiura_filiformis/.ResultsWe have identified highly conserved genes associated with the development of a biomineralised skeleton. We also identify important class-specific characters, including the independent duplication of the msp130 class of genes in different echinoderm classes and the unique occurrence of spicule matrix (sm) genes in echinoids. Using a new quantification pipeline for our de novo transcriptome, validated with other methodologies, we find major differences between brittle stars and sea urchins in the temporal expression of many transcription factor genes. This divergence in developmental regulatory states is more evident in early stages of development when cell specification begins, rather than when cells initiate differentiation.ConclusionsOur findings indicate that there has been a high degree of gene regulatory network rewiring and clade-specific gene duplication, supporting the hypothesis of a convergent evolution of larval skeleton development in echinoderms.

Gene Regulatory Network Rewiring in the Immune Cells Associated with Cancer.

The gene regulatory networks (GRNs) of immune cells not only indicate cell identity but also reveal the dynamic changes of immune cells when comparing their GRNs. Cancer immunotherapy has advanced in the past few years. Immune-checkpoint blockades (i.e., blocking PD-1, PD-L1, or CTLA-4) have shown durable clinical effects on some patients with various advanced cancers. However, major gaps in our knowledge of immunotherapy have been recognized. To fill these gaps, we conducted a systematic analysis of the GRNs of key immune cell subsets (i.e., B cell, CD4, CD8, CD8 naïve, CD8 Effector memory, CD8 Central Memory, regulatory T, Thelper1, Thelper2, Thelp17, and NK (Nature killer) and DC (Dendritic cell) cells associated with cancer immunologic therapies. We showed that most of the GRNs of these cells in blood share key important hub regulators, but their subnetworks for controlling cell type-specific receptors are different, suggesting that transformation between these immune cell subsets could be fast so that they can rapidly respond to environmental cues. To understand how cancer cells send molecular signals to immune cells to make them more cancer-cell friendly, we compared the GRNs of the tumor-infiltrating immune T cells and their corresponding immune cells in blood. We showed that the network size of the tumor-infiltrating immune T cells’ GRNs was reduced when compared to the GRNs of their corresponding immune cells in blood. These results suggest that the shutting down certain cellular activities of the immune cells by cancer cells is one of the key molecular mechanisms for helping cancer cells to escape the defense of the host immune system. These results highlight the possibility of genetic engineering of T cells for turning on the identified subnetworks that have been shut down by cancer cells to combat tumors.

Angiosperm Plant Desiccation Tolerance: Hints from Transcriptomics and Genome Sequencing.

Desiccation tolerance (DT) in angiosperms is present in the small group of resurrection plants and in seeds. DT requires the presence of protective proteins, specific carbohydrates, restructuring of membrane lipids, and regulatory mechanisms directing a dedicated gene expression program. Many components are common to resurrection plants and seeds; however, some are specific for resurrection plants. Understanding how each component contributes to DT is challenging. Recent transcriptome analyses and genome sequencing indicate that increased expression is essential of genes encoding protective components, recently evolved, species-specific genes and non-protein-coding RNAs. Modification and reshuffling of existing cis-regulatory promoter elements seems to play a role in the rewiring of regulatory networks required for increased expression of DT-related genes in resurrection species.