Dataset Information

Context specificity of the EMT transcriptional response.

ABSTRACT: Epithelial-mesenchymal plasticity contributes to many biological processes, including tumor progression. Various epithelial-mesenchymal transition (EMT) responses have been reported and no common, EMT-defining gene expression program has been identified. Here, we have performed a comparative analysis of the EMT response, leveraging highly multiplexed single-cell RNA sequencing (scRNA-seq) to measure expression profiles of 103,999 cells from 960 samples, comprising 12 EMT time course experiments and independent kinase inhibitor screens for each. We demonstrate that the EMT is vastly context specific, with an average of only 22% of response genes being shared between any two conditions, and over half of all response genes were restricted to 1-2 time course experiments. Further, kinase inhibitor screens revealed signaling dependencies and modularity of these responses. These findings suggest that the EMT is not simply a single, linear process, but is highly variable and modular, warranting quantitative frameworks for understanding nuances of the transition.

SUBMITTER: Cook DP

PROVIDER: S-EPMC7195456 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Context specificity of the EMT transcriptional response.

Cook David P DP Vanderhyden Barbara C BC

Nature communications 20200501 1

Epithelial-mesenchymal plasticity contributes to many biological processes, including tumor progression. Various epithelial-mesenchymal transition (EMT) responses have been reported and no common, EMT-defining gene expression program has been identified. Here, we have performed a comparative analysis of the EMT response, leveraging highly multiplexed single-cell RNA sequencing (scRNA-seq) to measure expression profiles of 103,999 cells from 960 samples, comprising 12 EMT time course experiments ...[more]

PMID: 32358524

Similar Datasets

Project description:The aim of this study was to analyze whether the activity of the autonomic nervous system (ANS) differs between two regrouping procedures in goats, which would indicate stimulus specificity of these stressors. Applying two regrouping procedures, we evaluated heart rate and heart rate variability (RMSSD, SDNN, and RMSSD/SDNN). The two regrouping procedures were (1) introduction of individual goats into established groups ("introduction experiment") and (2) temporary separation and subsequent reintegration of individuals from/into their group with two levels of contact during separation ("separation experiment"). In the "introduction experiment," the heart rate of introduced goats while lying decreased continuously from an average 78 to 68?beats/min from before the introduction to the last day of the introduction period. Inversely, RMSSD increased continuously from 41 to 62?ms, which, on its own, would indicate an adaptation to the situation. During the "separation experiment," heart rate while lying was higher when goats were separated in the "acoustic contact treatment" (82?beats/min on average) compared with the "restricted physical contact treatment" (75?beats/min on average). This difference reflected a higher level of arousal during the "acoustic contact treatment." However, heart rate activity did not allow detecting effects of separation or reintegration. Even though it can be assumed that both the separation and introduction of goats are stressful for goats, the ANS reactions observed in this study differed between the two management procedures indicating that the ANS activation was specific to each situation. In addition, we discuss the ANS results in context with earlier findings of variables of the hypothalamic pituitary adrenal (HPA) axis (fecal cortisol metabolites) and behavior (lying and feeding). As correspondence between ANS, HPA, and behavioral reactions was limited both within and across experiments, the results of this study underline the concept that stress response patterns are context specific.

Project description:Mammalian macrophages differ in their basal gene expression profiles and response to the toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS). In human macrophages, LPS elicits a temporal cascade of transient gene expression including feed forward activators and feedback regulators that limit the response. Here we present a transcriptional network analysis of the response of sheep bone marrow-derived macrophages (BMDM) to LPS based upon RNA-seq at 0, 2, 4, 7, and 24 h post-stimulation. The analysis reveals a conserved transcription factor network with humans, and rapid induction of feedback regulators that constrain the response at every level. The gene expression profiles of sheep BMDM at 0 and 7 h post LPS addition were compared to similar data obtained from goat, cow, water buffalo, horse, pig, mouse and rat BMDM. This comparison was based upon identification of 8,200 genes annotated in all species and detected at >10TPM in at least one sample. Analysis of expression of transcription factors revealed a conserved transcriptional millieu associated with macrophage differentiation and LPS response. The largest co-expression clusters, including genes encoding cell surface receptors, endosome-lysosome components and secretory activity, were also expressed in all species and the combined dataset defines a macrophage functional transcriptome. All of the large animals differed from rodents in lacking inducible expression of genes involved in arginine metabolism and nitric oxide production. Instead, they expressed inducible transporters and enzymes of tryptophan and kynurenine metabolism. BMDM from all species expressed high levels of transcripts encoding transporters and enzymes involved in glutamine metabolism suggesting that glutamine is a major metabolic fuel. We identify and discuss transcripts that were uniquely expressed or regulated in rodents compared to large animals including ACOD1, CXC and CC chemokines, CD163, CLEC4E, CPM, CSF1, CSF2, CTSK, MARCO, MMP9, SLC2A3, SLC7A7, and SUCNR1. Conversely, the data confirm the conserved regulation of multiple transcripts for which there is limited functional data from mouse models and knockouts. The data provide a resource for functional annotation and interpretation of loci involved in susceptibility to infectious and inflammatory disease in humans and large animal species.

Project description:Spatiotemporally precise and robust cell fate transitions, which depend on specific signaling cues, are fundamental to the development of appropriately patterned tissues. The fidelity and precision with which photoreceptor fates are recruited in the Drosophila eye exemplifies these principles. The fly eye consists of a highly ordered array of ~750 ommatidia, each of which contains eight distinct photoreceptors, R1-R8, specified sequentially in a precise spatial pattern. Recruitment of R1-R7 fates requires reiterative receptor tyrosine kinase / mitogen activated protein kinase (MAPK) signaling mediated by the transcriptional effector Pointed (Pnt). However the overall signaling levels experienced by R2-R5 cells are distinct from those experienced by R1, R6 and R7. A relay mechanism between two Pnt isoforms initiated by MAPK activation directs the universal transcriptional response. Here we ask how the generic Pnt response is tailored to these two rounds of photoreceptor fate transitions. We find that during R2-R5 specification PntP2 is coexpressed with a closely related but previously uncharacterized isoform, PntP3. Using CRISPR/Cas9-generated isoform specific null alleles we show that under otherwise wild type conditions, R2-R5 fate specification is robust to loss of either PntP2 or PntP3, and that the two activate pntP1 redundantly; however under conditions of reduced MAPK activity, both are required. Mechanistically, our data suggest that intrinsic activity differences between PntP2 and PntP3, combined with positive and unexpected negative transcriptional auto- and cross-regulation, buffer first-round fates against conditions of compromised RTK signaling. In contrast, in a mechanism that may be adaptive to the stronger signaling environment used to specify R1, R6 and R7 fates, the Pnt network resets to a simpler topology in which PntP2 uniquely activates pntP1 and auto-activates its own transcription. We propose that differences in expression patterns, transcriptional activities and regulatory interactions between Pnt isoforms together facilitate context-appropriate cell fate specification in different signaling environments.

Dataset Information

Context specificity of the EMT transcriptional response.

Publications

Context specificity of the EMT transcriptional response.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets