scholarly journals Discovering the chlamydospore regulatory network in Candida albicans

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Priyanka Bapat ◽  
Clarissa Nobile
Keyword(s):  
Regulatory Network ◽  
Target Genes ◽  
Pathogenic Fungus ◽  
Selective Advantage ◽  
Growth Conditions ◽  
Homozygous Deletion ◽  
Rna Seq ◽  
Healthy Humans ◽  
Chlamydospore Formation ◽  
Transcriptional Changes

A normal resident of healthy humans and warm-blooded animals, C. albicans is a commensal fungus that is also among the most common opportunistic pathogens of humans. C. albicans forms unique morphological structures called chlamydospores, which are large, spherical, thick-walled structures formed at the ends of hyphae that have unknown biological function. My goal is to discover the regulatory network controlling chlamydospore formation in C. albicans. By determining this network, we can gain insight into the biological roles of chlamydospores in the C. albicans lifestyle, better understand C. albicans morphological transitions, and determine the selective advantage (if any) provided by chlamydospores to this pathogenic fungus. To determine this regulatory network, I have screened a library of 211 C. albicans transcription factor (TF) homozygous deletion mutants to assay for their abilities to form chlamydospores under standard chlamydospore-inducing growth conditions. I have identified seven TF mutants that fail to produce any chlamydospores andthree TF mutants that produce high levels of chlamydospores relative to WT. To characterize the transcriptional changes occurring during chlamydospore formation, I have performed RNA sequencing (RNA-seq) on these identified regulator mutants to uncover the differentially regulated target genes of each chlamydospore regulator. I will use genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq) on epitope-tagged versions of these regulators to determine which genes are directly under the control of each TF. RNA-seq coupled with ChIP-seq will allow me to determine the regulatory network controlling chlamydospore formation in C. albicans.

scholarly journals Genome-wide phylogenetic analysis, expression pattern, and transcriptional regulatory network of the pig C/EBP gene family

2020 ◽  
Author(s):  
Chaoxin Zhang ◽  
Tao Wang ◽  
Shengwei Liu ◽  
Bing Zhang ◽  
Xue Li ◽  
...  
Keyword(s):  
Phylogenetic Analysis ◽  
Regulatory Network ◽  
Target Genes ◽  
Transcriptional Regulatory Network ◽  
Expression Patterns ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Rna Seq ◽  
Group I

Abstract Background: The vertebrate C/EBP transcription factors regulate many important biological processes, such as cell proliferation, differentiation, signal transduction, inflammation, and energy metabolism. The first C/EBP protein was identified in rat liver nuclei. Development of sequencing technology resulted in identification of the C/EBP genes in various species. In this study, a bioinformatics approach was used to determine the distribution of the members of the C/EBP family in vertebrates. A phylogenetic tree was constructed to analyze the C/EBP genes in vertebrates. Based on RNA-seq data, the expression patterns of pig C/EBP members in various tissues were analyzed. In addition, a gene transcription regulatory network was constructed with pig C/EBP members as the core.Results: We identified a total of 92 C/EBP genes in 17 vertebrate genomes. Phylogenetic analysis showed that all C/EBP TFs were classified into two groups; group I contained C/EBPβ TFs, and group II contained the remaining C/EBP TFs. The C/EBPα, C/EBPβ, C/EBPδ, C/EBPγ, and C/EBPζ genes were expressed ubiquitously with inconsistent expression patterns in various tissues. Moreover, a pig C/EBP regulatory network was constructed, including C/EBP genes, TFs, and miRNAs. A total of 39 FFL motifs were detected in the pig C/EBP regulatory network. Based on the RNA-seq data, gene expression patterns related to this FFL sub-network were analyzed in 27 adult Duroc tissues. Certain FFL motifs may be tissue specific. Functional enrichment analysis indicated that C/EBP and its target genes are involved in many important biological pathways. Conclusions: These results provide valuable information that clarifies the evolutionary relationships of the C/EBP family and contributes to the understanding of the biological function of C/EBP genes.

scholarly journals SCENIC: Single-cell regulatory network inference and clustering

2017 ◽  
Author(s):  
Sara Aibar ◽  
Carmen Bravo González-Blas ◽  
Thomas Moerman ◽  
Jasper Wouters ◽  
Vân Anh Huynh-Thu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Single Cell ◽  
Regulatory Network ◽  
Network Inference ◽  
Target Genes ◽  
Single Cells ◽  
State Transitions ◽  
Rna Seq ◽  
Cell State ◽  
Gene Regulatory

AbstractSingle-cell RNA-seq allows building cell atlases of any given tissue and infer the dynamics of cellular state transitions during developmental or disease trajectories. Both the maintenance and transitions of cell states are encoded by regulatory programs in the genome sequence. However, this regulatory code has not yet been exploited to guide the identification of cellular states from single-cell RNA-seq data. Here we describe a computational resource, called SCENIC (Single Cell rEgulatory Network Inference and Clustering), for the simultaneous reconstruction of gene regulatory networks (GRNs) and the identification of stable cell states, using single-cell RNA-seq data. SCENIC outperforms existing approaches at the level of cell clustering and transcription factor identification. Importantly, we show that cell state identification based on GRNs is robust towards batch-effects and technical-biases. We applied SCENIC to a compendium of single-cell data from the mouse and human brain and demonstrate that the proper combinations of transcription factors, target genes, enhancers, and cell types can be identified. Moreover, we used SCENIC to map the cell state landscape in melanoma and identified a gene regulatory network underlying a proliferative melanoma state driven by MITF and STAT and a contrasting network controlling an invasive state governed by NFATC2 and NFIB. We further validated these predictions by showing that two transcription factors are predominantly expressed in early metastatic sentinel lymph nodes. In summary, SCENIC is the first method to analyze scRNA-seq data using a network-centric, rather than cell-centric approach. SCENIC is generic, easy to use, and flexible, and allows for the simultaneous tracing of genomic regulatory programs and the mapping of cellular identities emerging from these programs. Availability: SCENIC is available as an R workflow based on three new R/Bioconductor packages: GENIE3, RcisTarget and AUCell. As scalable alternative to GENIE3, we also provide GRNboost, paving the way towards the network analysis across millions of single cells.

scholarly journals Regulation of gene expression by the APP family in the adult cerebral cortex

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Hye Ji Cha ◽  
Jie Shen ◽  
Jongkyun Kang
Keyword(s):  
Gene Expression ◽  
Cerebral Cortex ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Mrna Levels ◽  
Rna Seq ◽  
Cellular Functions ◽  
Organization Learning ◽  
Transcriptional Changes

AbstractAmyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer’s disease. APP has two homologs, amyloid precursor-like protein 1 and 2 (APLP1 and APLP2), and they have functional redundancy. APP intracellular c-terminal domain (AICD), produced by sequential α- or β- and γ-secretase cleavages, is thought to control gene expression, similarly as the ICD of Notch. To investigate the role of APP family in transcriptional regulation, we examined gene expression changes in the cerebral cortex of APP/APLP1/APLP2 conditional triple knockout (cTKO) mice, in which APP family members are selectively inactivated in excitatory neurons of the postnatal forebrain. Of the 12 previously reported AICD target genes, only Nep and Npas4 mRNA levels were significantly reduced in the cerebral cortex of cTKO mice, compared to littermate controls. We further examined global transcriptional changes by RNA-seq and identified 189 and 274 differentially expressed genes in the neocortex and hippocampus, respectively, of cTKO mice relative to controls. Gene Ontology analysis indicated that these genes are involved in a variety of cellular functions, including extracellular organization, learning and memory, and ion channels. Thus, inactivation of APP family alters transcriptional profiles of the cerebral cortex and affects wide-ranging molecular pathways.

scholarly journals MicroRNAs Involved in Regulatory Cytoplasmic Male Sterility by Analysis RNA-seq and Small RNA-seq in Soybean

2021 ◽  
Vol 12 ◽  
Author(s):  
Chunbao Zhang ◽  
Fuyou Fu ◽  
Chunjing Lin ◽  
Xiaoyang Ding ◽  
Jingyong Zhang ◽  
...  
Keyword(s):  
Cytoplasmic Male Sterility ◽  
Male Sterility ◽  
Regulatory Network ◽  
Target Genes ◽  
Reproductive Development ◽  
Differentially Expressed ◽  
Hybrid Breeding ◽  
Rna Seq ◽  
Maintainer Line ◽  
Cms Line

Cytoplasmic male sterility (CMS) is an important plant characteristic for exploiting heterosis to enhance crop traits during breeding. However, the CMS regulatory network remains unclear in plants, even though researchers have attempted to isolate genes associated with CMS. In this study, we performed high-throughput sequencing and degradome analyses to identify microRNAs (miRNAs) and their targets in a soybean CMS line (JLCMS9A) and its maintainer line (JLCMS9B). Additionally, the differentially expressed genes during reproductive development were identified using RNA-seq data. A total of 280 miRNAs matched soybean miRNA sequences in miRBase, including mature miRNAs and pre-miRNAs. Of the 280 miRNAs, 30, 23, and 21 belonged to the miR166, miR156, and miR171 families, respectively. Moreover, 410 novel low-abundant miRNAs were identified in the JLCMS9A and JLCMS9B flower buds. Furthermore, 303 and 462 target genes unique to JLCMS9A and JLCMS9B, respectively, as well as 782 common targets were predicted based on the degradome analysis. Target genes differentially expressed between the CMS line and the maintainer line were revealed by an RNA-seq analysis. Moreover, all target genes were annotated with diverse functions related to biological processes, cellular components, and molecular functions, including transcriptional regulation, the nucleus, meristem maintenance, meristem initiation, cell differentiation, auxin-activated signaling, plant ovule development, and anther development. Finally, a network was built based on the interactions. Analyses of the miRNA, degradome, and transcriptome datasets generated in this study provided a comprehensive overview of the reproductive development of a CMS soybean line. The data presented herein represent useful information for soybean hybrid breeding. Furthermore, the study results indicate that miRNAs might contribute to the soybean CMS regulatory network by modulating the expression of CMS-related genes. These findings lay the foundation for future studies on the molecular mechanisms underlying soybean CMS.

scholarly journals Dissecting the pre-placodal transcriptome to reveal presumptive direct targets of Six1 and Eya1 in cranial placodes

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Nick Riddiford ◽  
Gerhard Schlosser
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Regulatory Network ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Transcriptional Regulators ◽  
Rna Seq ◽  
Loss Of Function ◽  
Genes Encoding ◽  
Gene Regulatory

The pre-placodal ectoderm, marked by the expression of the transcription factor Six1 and its co-activator Eya1, develops into placodes and ultimately into many cranial sensory organs and ganglia. Using RNA-Seq in Xenopus laevis we screened for presumptive direct placodal target genes of Six1 and Eya1 by overexpressing hormone-inducible constructs of Six1 and Eya1 in pre-placodal explants, and blocking protein synthesis before hormone-inducing nuclear translocation of Six1 or Eya1. Comparing the transcriptome of explants with non-induced controls, we identified hundreds of novel Six1/Eya1 target genes with potentially important roles for placode development. Loss-of-function studies confirmed that target genes encoding known transcriptional regulators of progenitor fates (e.g. Sox2, Hes8) and neuronal/sensory differentiation (e.g. Ngn1, Atoh1, Pou4f1, Gfi1) require Six1 and Eya1 for their placodal expression. Our findings provide insights into the gene regulatory network regulating placodal neurogenesis downstream of Six1 and Eya1 suggesting new avenues of research into placode development and disease.

scholarly journals NKL Homeobox Gene VENTX Is Part of a Regulatory Network in Human Conventional Dendritic Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5902
Author(s):  
Stefan Nagel ◽  
Claudia Pommerenke ◽  
Corinna Meyer ◽  
Hans G. Drexler
Keyword(s):  
Dendritic Cells ◽  
Transcription Factors ◽  
Cell Lines ◽  
Expression Profiling ◽  
Regulatory Network ◽  
Homeobox Gene ◽  
Leukemia Cell Line ◽  
Specific Gene ◽  
Rna Seq ◽  
And Function

Recently, we documented a hematopoietic NKL-code mapping physiological expression patterns of NKL homeobox genes in human myelopoiesis including monocytes and their derived dendritic cells (DCs). Here, we enlarge this map to include normal NKL homeobox gene expressions in progenitor-derived DCs. Analysis of public gene expression profiling and RNA-seq datasets containing plasmacytoid and conventional dendritic cells (pDC and cDC) demonstrated HHEX activity in both entities while cDCs additionally expressed VENTX. The consequent aim of our study was to examine regulation and function of VENTX in DCs. We compared profiling data of VENTX-positive cDC and monocytes with VENTX-negative pDC and common myeloid progenitor entities and revealed several differentially expressed genes encoding transcription factors and pathway components, representing potential VENTX regulators. Screening of RNA-seq data for 100 leukemia/lymphoma cell lines identified prominent VENTX expression in an acute myelomonocytic leukemia cell line, MUTZ-3 containing inv(3)(q21q26) and t(12;22)(p13;q11) and representing a model for DC differentiation studies. Furthermore, extended gene analyses indicated that MUTZ-3 is associated with the subtype cDC2. In addition to analysis of public chromatin immune-precipitation data, subsequent knockdown experiments and modulations of signaling pathways in MUTZ-3 and control cell lines confirmed identified candidate transcription factors CEBPB, ETV6, EVI1, GATA2, IRF2, MN1, SPIB, and SPI1 and the CSF-, NOTCH-, and TNFa-pathways as VENTX regulators. Live-cell imaging analyses of MUTZ-3 cells treated for VENTX knockdown excluded impacts on apoptosis or induced alteration of differentiation-associated cell morphology. In contrast, target gene analysis performed by expression profiling of knockdown-treated MUTZ-3 cells revealed VENTX-mediated activation of several cDC-specific genes including CSFR1, EGR2, and MIR10A and inhibition of pDC-specific genes like RUNX2. Taken together, we added NKL homeobox gene activities for progenitor-derived DCs to the NKL-code, showing that VENTX is expressed in cDCs but not in pDCs and forms part of a cDC-specific gene regulatory network operating in DC differentiation and function.

scholarly journals EPEN-21. IMPAIRED NEURONAL-GLIAL FATE SPECIFICATION IN PEDIATRIC EPENDYMOMA REVEALED BY SINGLE-CELL RNA-SEQ

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii311-iii312
Author(s):  
Bernhard Englinger ◽  
Johannes Gojo ◽  
Li Jiang ◽  
Jens M Hübner ◽  
McKenzie L Shaw ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Cell ◽  
Regulatory Networks ◽  
Target Genes ◽  
Target Identification ◽  
Rna Seq ◽  
Cell Models ◽  
Pediatric Ependymoma ◽  
Glial Fate ◽  
Anatomic Locations

Abstract Ependymoma represents a heterogeneous disease affecting the entire neuraxis. Extensive molecular profiling efforts have identified molecular ependymoma subgroups based on DNA methylation. However, the intratumoral heterogeneity and developmental origins of these groups are only partially understood, and effective treatments are still lacking for about 50% of patients with high-risk tumors. We interrogated the cellular architecture of ependymoma using single cell/nucleus RNA-sequencing to analyze 24 tumor specimens across major molecular subgroups and anatomic locations. We additionally analyzed ten patient-derived ependymoma cell models and two patient-derived xenografts (PDXs). Interestingly, we identified an analogous cellular hierarchy across all ependymoma groups, originating from undifferentiated neural stem cell-like populations towards different degrees of impaired differentiation states comprising neuronal precursor-like, astro-glial-like, and ependymal-like tumor cells. While prognostically favorable ependymoma groups predominantly harbored differentiated cell populations, aggressive groups were enriched for undifferentiated subpopulations. Projection of transcriptomic signatures onto an independent bulk RNA-seq cohort stratified patient survival even within known molecular groups, thus refining the prognostic power of DNA methylation-based profiling. Furthermore, we identified novel potentially druggable targets including IGF- and FGF-signaling within poorly prognostic transcriptional programs. Ependymoma-derived cell models/PDXs widely recapitulated the transcriptional programs identified within fresh tumors and are leveraged to validate identified target genes in functional follow-up analyses. Taken together, our analyses reveal a developmental hierarchy and transcriptomic context underlying the biologically and clinically distinct behavior of ependymoma groups. The newly characterized cellular states and underlying regulatory networks could serve as basis for future therapeutic target identification and reveal biomarkers for clinical trials.

scholarly journals Regulatory Network Analysis in Estradiol-Treated Human Endothelial Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8193
Author(s):  
Daniel Pérez-Cremades ◽  
Ana B. Paes ◽  
Xavier Vidal-Gómez ◽  
Ana Mompeón ◽  
Carlos Hermenegildo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Mirna Target ◽  
Target Genes ◽  
Functional Characterization ◽  
Human Endothelial Cells ◽  
Mrna Targets ◽  
Canonical Pathways

Background/Aims: Estrogen has been reported to have beneficial effects on vascular biology through direct actions on endothelium. Together with transcription factors, miRNAs are the major drivers of gene expression and signaling networks. The objective of this study was to identify a comprehensive regulatory network (miRNA-transcription factor-downstream genes) that controls the transcriptomic changes observed in endothelial cells exposed to estradiol. Methods: miRNA/mRNA interactions were assembled using our previous microarray data of human umbilical vein endothelial cells (HUVEC) treated with 17β-estradiol (E2) (1 nmol/L, 24 h). miRNA–mRNA pairings and their associated canonical pathways were determined using Ingenuity Pathway Analysis software. Transcription factors were identified among the miRNA-regulated genes. Transcription factor downstream target genes were predicted by consensus transcription factor binding sites in the promoter region of E2-regulated genes by using JASPAR and TRANSFAC tools in Enrichr software. Results: miRNA–target pairings were filtered by using differentially expressed miRNAs and mRNAs characterized by a regulatory relationship according to miRNA target prediction databases. The analysis identified 588 miRNA–target interactions between 102 miRNAs and 588 targets. Specifically, 63 upregulated miRNAs interacted with 295 downregulated targets, while 39 downregulated miRNAs were paired with 293 upregulated mRNA targets. Functional characterization of miRNA/mRNA association analysis highlighted hypoxia signaling, integrin, ephrin receptor signaling and regulation of actin-based motility by Rho among the canonical pathways regulated by E2 in HUVEC. Transcription factors and downstream genes analysis revealed eight networks, including those mediated by JUN and REPIN1, which are associated with cadherin binding and cell adhesion molecule binding pathways. Conclusion: This study identifies regulatory networks obtained by integrative microarray analysis and provides additional insights into the way estradiol could regulate endothelial function in human endothelial cells.

scholarly journals Distinct regulation of hippocampal neuroplasticity and ciliary genes by corticosteroid receptors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Karen R. Mifsud ◽  
Clare L. M. Kennedy ◽  
Silvia Salatino ◽  
Eshita Sharma ◽  
Emily M. Price ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Glucocorticoid Receptors ◽  
Acute Stress ◽  
Circadian Variation ◽  
Rna Seq ◽  
Physiological Regulation ◽  
Behavioural Adaptation ◽  
Neuronal Progenitor ◽  
Genome Wide ◽  
Transcriptional Changes

AbstractGlucocorticoid hormones (GCs) — acting through hippocampal mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) — are critical to physiological regulation and behavioural adaptation. We conducted genome-wide MR and GR ChIP-seq and Ribo-Zero RNA-seq studies on rat hippocampus to elucidate MR- and GR-regulated genes under circadian variation or acute stress. In a subset of genes, these physiological conditions resulted in enhanced MR and/or GR binding to DNA sequences and associated transcriptional changes. Binding of MR at a substantial number of sites however remained unchanged. MR and GR binding occur at overlapping as well as distinct loci. Moreover, although the GC response element (GRE) was the predominant motif, the transcription factor recognition site composition within MR and GR binding peaks show marked differences. Pathway analysis uncovered that MR and GR regulate a substantial number of genes involved in synaptic/neuro-plasticity, cell morphology and development, behavior, and neuropsychiatric disorders. We find that MR, not GR, is the predominant receptor binding to >50 ciliary genes; and that MR function is linked to neuronal differentiation and ciliogenesis in human fetal neuronal progenitor cells. These results show that hippocampal MRs and GRs constitutively and dynamically regulate genomic activities underpinning neuronal plasticity and behavioral adaptation to changing environments.

scholarly journals Activation of the p11/SMARCA3/Neurensin-2 pathway in parvalbumin interneurons mediates the response to chronic antidepressants

2021 ◽  
Author(s):  
Gali Umschweif ◽  
Lucian Medrihan ◽  
Kathryn A. McCabe ◽  
Yotam Sagi ◽  
Paul Greengard
Keyword(s):  
Chromatin Remodeling ◽  
Behavioral Response ◽  
Hippocampal Neurons ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Chronic Treatment ◽  
Target Genes ◽  
Delayed Response ◽  
Dynamic Changes ◽  
Parvalbumin Interneurons ◽  
Transcriptional Changes

AbstractThe delayed behavioral response to chronic antidepressants depends on dynamic changes in the hippocampus. It was suggested that the antidepressant protein p11 and the chromatin remodeling factor SMARCA3 mediate this delayed response by inducing transcriptional changes in hippocampal neurons. However, what target genes are regulated by the p11/SMARCA3 complex to mediate the behavioral response to antidepressants, and what cell type mediates these molecular changes remain unknown. Here we report that the p11/SMARCA3 complex represses Neurensin-2 transcription in hippocampal parvalbumin-expressing interneurons after chronic treatment with Selective Serotonin Reuptake Inhibitors (SSRI). The behavioral response to antidepressants requires upregulation of p11, accumulation of SMARCA3 in the cell nucleus, and a consequent repression of Neurensin-2 transcription in these interneurons. We elucidate a functional role for p11/SMARCA3/Neurensin-2 pathway in regulating AMPA-receptor signaling in parvalbumin-expressing interneurons, a function that is enhanced by chronic treatment with SSRIs. These results link SSRIs to dynamic glutamatergic changes and implicate p11/SMARCA3/Neurensin-2 pathway in the development of more specific and efficient therapeutic strategies for neuropsychiatric disorders.

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