scholarly journals Single-cell gene regulatory network analysis reveals new melanoma cell states and transition trajectories during phenotype switching

2019 ◽  
Author(s):  
Jasper Wouters ◽  
Zeynep Kalender-Atak ◽  
Liesbeth Minnoye ◽  
Katina I. Spanier ◽  
Maxime De Waegeneer ◽  
...  
Keyword(s):  
Single Cell ◽  
Gene Regulatory Network ◽  
Melanoma Cell ◽  
Intermediate State ◽  
Regulatory Network ◽  
Mesenchymal Cell ◽  
Melanoma Cells ◽  
Cell State ◽  
Gene Regulatory ◽  
Phenotype Switching

AbstractMelanoma is notorious for its cellular heterogeneity, which is at least partly due to its ability to transition between alternate cell states. Similarly to EMT, melanoma cells with a melanocytic phenotype can switch to a mesenchymal-like phenotype. However, scattered emerging evidence indicates that additional, intermediate state(s) may exist. In order to search for such new melanoma states and decipher their underlying gene regulatory network (GRN), we extensively studied ten patient-derived melanoma cultures by single-cell RNA-seq of >39,000 cells. Although each culture exhibited a unique transcriptome, we identified shared gene regulatory networks that underlie the extreme melanocytic and mesenchymal cell states, as well as one (stable) intermediate state. The intermediate state was corroborated by a distinct open chromatin landscape and governed by the transcription factors EGR3, NFATC2, and RXRG. Single-cell migration assays established that this “transition” state exhibits an intermediate migratory phenotype. Through a dense time-series sampling of single cells and dynamic GRN inference, we unraveled the sequential and recurrent arrangement of transcriptional programs at play during phenotype switching that ultimately lead to the mesenchymal cell state. We provide the scRNA-Seq data with 39,263 melanoma cells on our SCope platform and the ATAC-seq data on a UCSC hub to jointly serve as a resource for the melanoma field. Together, this exhaustive analysis of melanoma cell state diversity indicates that additional states exists between the two extreme melanocytic and mesenchymal-like states. The GRN we identified may serve as a new putative target to prevent the switch to mesenchymal cell state and thereby, acquisition of metastatic and drug resistant potential.

SIN-KNO: A method of gene regulatory network inference using single-cell transcription and gene knockout data

2019 ◽  
Vol 17 (06) ◽  
pp. 1950035
Author(s):  
Huiqing Wang ◽  
Yuanyuan Lian ◽  
Chun Li ◽  
Yue Ma ◽  
Zhiliang Yan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Steady State ◽  
Single Cell ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Gene Knockout ◽  
Cell Heterogeneity ◽  
State Information ◽  
Gene Regulatory ◽  
Cell Data

As a tool of interpreting and analyzing genetic data, gene regulatory network (GRN) could reveal regulatory relationships between genes, proteins, and small molecules, as well as understand physiological activities and functions within biological cells, interact in pathways, and how to make changes in the organism. Traditional GRN research focuses on the analysis of the regulatory relationships through the average of cellular gene expressions. These methods are difficult to identify the cell heterogeneity of gene expression. Existing methods for inferring GRN using single-cell transcriptional data lack expression information when genes reach steady state, and the high dimensionality of single-cell data leads to high temporal and spatial complexity of the algorithm. In order to solve the problem in traditional GRN inference methods, including the lack of cellular heterogeneity information, single-cell data complexity and lack of steady-state information, we propose a method for GRN inference using single-cell transcription and gene knockout data, called SINgle-cell transcription data-KNOckout data (SIN-KNO), which focuses on combining dynamic and steady-state information of regulatory relationship contained in gene expression. Capturing cell heterogeneity information could help understand the gene expression difference in different cells. So, we could observe gene expression changes more accurately. Gene knockout data could observe the gene expression levels at steady-state of all other genes when one gene is knockout. Classifying the genes before analyzing the single-cell data could determine a large number of non-existent regulation, greatly reducing the number of regulation required for inference. In order to show the efficiency, the proposed method has been compared with several typical methods in this area including GENIE3, JUMP3, and SINCERITIES. The results of the evaluation indicate that the proposed method can analyze the diversified information contained in the two types of data, establish a more accurate gene regulation network, and improve the computational efficiency. The method provides a new thinking for dealing with large datasets and high computational complexity of single-cell data in the GRN inference.

scholarly journals Benchmarking algorithms for gene regulatory network inference from single-cell transcriptomic data

2020 ◽  
Vol 17 (2) ◽  
pp. 147-154 ◽  
Author(s):  
Aditya Pratapa ◽  
Amogh P. Jalihal ◽  
Jeffrey N. Law ◽  
Aditya Bharadwaj ◽  
T. M. Murali
Keyword(s):  
Single Cell ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Network Inference ◽  
Gene Regulatory Network Inference ◽  
Transcriptomic Data ◽  
Gene Regulatory

scholarly journals Gene regulatory network reconstruction using single-cell RNA sequencing of barcoded genotypes in diverse environments

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Christopher A Jackson ◽  
Dayanne M Castro ◽  
Giuseppe-Antonio Saldi ◽  
Richard Bonneau ◽  
David Gresham
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Rna Sequencing ◽  
Gene Regulatory Network ◽  
Gene Regulatory Networks ◽  
Regulatory Network ◽  
Regulatory Networks ◽  
Target Genes ◽  
Single Cell Rna Sequencing ◽  
Gene Regulatory

Understanding how gene expression programs are controlled requires identifying regulatory relationships between transcription factors and target genes. Gene regulatory networks are typically constructed from gene expression data acquired following genetic perturbation or environmental stimulus. Single-cell RNA sequencing (scRNAseq) captures the gene expression state of thousands of individual cells in a single experiment, offering advantages in combinatorial experimental design, large numbers of independent measurements, and accessing the interaction between the cell cycle and environmental responses that is hidden by population-level analysis of gene expression. To leverage these advantages, we developed a method for scRNAseq in budding yeast (Saccharomyces cerevisiae). We pooled diverse transcriptionally barcoded gene deletion mutants in 11 different environmental conditions and determined their expression state by sequencing 38,285 individual cells. We benchmarked a framework for learning gene regulatory networks from scRNAseq data that incorporates multitask learning and constructed a global gene regulatory network comprising 12,228 interactions.

scholarly journals A single cell RNA sequencing resource for early sea urchin development

Development ◽  
2020 ◽  
Vol 147 (17) ◽  
pp. dev191528 ◽  
Author(s):  
Stephany Foster ◽  
Nathalie Oulhen ◽  
Gary Wessel
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Gene Regulatory Network ◽  
Sea Urchin ◽  
Germ Cells ◽  
Regulatory Network ◽  
Germ Line ◽  
Primordial Germ Cells ◽  
Single Cell Rna Sequencing ◽  
Gene Regulatory

ABSTRACTIdentifying cell states during development from their mRNA profiles provides insight into their gene regulatory network. Here, we leverage the sea urchin embryo for its well-established gene regulatory network to interrogate the embryo using single cell RNA sequencing. We tested eight developmental stages in Strongylocentrotus purpuratus, from the eight-cell stage to late in gastrulation. We used these datasets to parse out 22 major cell states of the embryo, focusing on key transition stages for cell type specification of each germ layer. Subclustering of these major embryonic domains revealed over 50 cell states with distinct transcript profiles. Furthermore, we identified the transcript profile of two cell states expressing germ cell factors, one we conclude represents the primordial germ cells and the other state is transiently present during gastrulation. We hypothesize that these cells of the Veg2 tier of the early embryo represent a lineage that converts to the germ line when the primordial germ cells are deleted. This broad resource will hopefully enable the community to identify other cell states and genes of interest to expose the underpinning of developmental mechanisms.

scholarly journals scSGL: Signed Graph Learning for Single-Cell Gene Regulatory Network Inference

2021 ◽  
Author(s):  
Abdullah Karaaslanli ◽  
Satabdi Saha ◽  
Selin Aviyente ◽  
Tapabrata Maiti
Keyword(s):  
Single Cell ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Gene Networks ◽  
Signed Graph ◽  
Reconstruction Algorithms ◽  
Gene Regulatory Network Inference ◽  
Graph Learning ◽  
Gene Regulatory ◽  
Cell Gene

Elucidating the topology of gene regulatory networks (GRN) from large single-cell RNA sequencing (scRNAseq) datasets, while effectively capturing its inherent cell-cycle heterogeneity, is currently one of the most pressing problems in computational systems biology. Recently, graph learning (GL) approaches based on graph signal processing (GSP) have been developed to infer graph topology from signals defined on graphs. However, existing GL methods are not suitable for learning signed graphs, which represent a characteristic feature of GRNs, as they account for both activating and inhibitory relationships between genes. To this end, we propose a novel signed GL approach, scSGL, that incorporates the similarity and dissimilarity between observed gene expression data to construct gene networks. The proposed approach is formulated as a non-convex optimization problem and solved using an efficient ADMM framework. In our experiments on simulated and real single cell datasets, scSGL compares favorably with other single cell gene regulatory network reconstruction algorithms.

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