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      Mapping gene regulatory networks from single-cell omics data

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          Abstract

          Single-cell techniques are advancing rapidly and are yielding unprecedented insight into cellular heterogeneity. Mapping the gene regulatory networks (GRNs) underlying cell states provides attractive opportunities to mechanistically understand this heterogeneity. In this review, we discuss recently emerging methods to map GRNs from single-cell transcriptomics data, tackling the challenge of increased noise levels and data sparsity compared with bulk data, alongside increasing data volumes. Next, we discuss how new techniques for single-cell epigenomics, such as single-cell ATAC-seq and single-cell DNA methylation profiling, can be used to decipher gene regulatory programmes. We finally look forward to the application of single-cell multi-omics and perturbation techniques that will likely play important roles for GRN inference in the future.

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          Most cited references39

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          Comparative Analysis of Single-Cell RNA Sequencing Methods.

          Single-cell RNA sequencing (scRNA-seq) offers new possibilities to address biological and medical questions. However, systematic comparisons of the performance of diverse scRNA-seq protocols are lacking. We generated data from 583 mouse embryonic stem cells to evaluate six prominent scRNA-seq methods: CEL-seq2, Drop-seq, MARS-seq, SCRB-seq, Smart-seq, and Smart-seq2. While Smart-seq2 detected the most genes per cell and across cells, CEL-seq2, Drop-seq, MARS-seq, and SCRB-seq quantified mRNA levels with less amplification noise due to the use of unique molecular identifiers (UMIs). Power simulations at different sequencing depths showed that Drop-seq is more cost-efficient for transcriptome quantification of large numbers of cells, while MARS-seq, SCRB-seq, and Smart-seq2 are more efficient when analyzing fewer cells. Our quantitative comparison offers the basis for an informed choice among six prominent scRNA-seq methods, and it provides a framework for benchmarking further improvements of scRNA-seq protocols.
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            Single cell RNA Seq reveals dynamic paracrine control of cellular variation

            High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis, and function of gene expression variation between seemingly identical cells. Here, we sequence single-cell RNA-Seq libraries prepared from over 1,700 primary mouse bone marrow derived dendritic cells (DCs) spanning several experimental conditions. We find substantial variation between identically stimulated DCs, in both the fraction of cells detectably expressing a given mRNA and the transcript’s level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a “core” module of antiviral genes is expressed very early by a few “precocious” cells, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analyzing DCs from knockout mice, and modulating secretion and extracellular signaling, we show that this response is coordinated via interferon-mediated paracrine signaling. Surprisingly, preventing cell-to-cell communication also substantially reduces variability in the expression of an early-induced “peaked” inflammatory module, suggesting that paracrine signaling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations use to establish complex dynamic responses.
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              Modelling and analysis of gene regulatory networks.

              Gene regulatory networks have an important role in every process of life, including cell differentiation, metabolism, the cell cycle and signal transduction. By understanding the dynamics of these networks we can shed light on the mechanisms of diseases that occur when these cellular processes are dysregulated. Accurate prediction of the behaviour of regulatory networks will also speed up biotechnological projects, as such predictions are quicker and cheaper than lab experiments. Computational methods, both for supporting the development of network models and for the analysis of their functionality, have already proved to be a valuable research tool.
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                Author and article information

                Journal
                Brief Funct Genomics
                Brief Funct Genomics
                bfgp
                Briefings in Functional Genomics
                Oxford University Press
                2041-2649
                2041-2657
                July 2018
                12 January 2018
                12 January 2018
                : 17
                : 4 , Special Issue: Single-cell genomics
                : 246-254
                Affiliations
                [1 ]VIB Center for Brain & Disease Research, Laboratory of Computational Biology, Leuven, Belgium
                [2 ]KU Leuven, Department of Human Genetics, Leuven, Belgium
                Author notes
                Corresponding author: Stein Aerts, VIB Center for Brain & Disease Research, Laboratory of Computational Biology and KU Leuven, Department of Human Genetics, Herestraat 49, box 602, 3000 Leuven, Belgium. E-mail: stein.aerts@ 123456kuleuven.vib.be

                Mark W.E.J Fiers, Liesbeth Minnoye and Sara Aibar authors contributed to this work equally.

                Author information
                http://orcid.org/0000-0001-5694-2409
                Article
                elx046
                10.1093/bfgp/elx046
                6063279
                29342231
                986919de-601f-4b88-b0ef-124aece2923d
                © The Author(s) 2018. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Page count
                Pages: 9
                Funding
                Funded by: The Research Foundation – Flanders
                Award ID: G.0640.13
                Award ID: G.0791.14
                Award ID: G092916N
                Funded by: Special Research Fund 10.13039/501100007229
                Funded by: KU Leuven 10.13039/501100004040
                Award ID: PF/10/016
                Award ID: OT/13/103
                Funded by: Foundation Against Cancer
                Award ID: 2012-F2
                Award ID: 2016-070
                Award ID: 2015-143
                Funded by: ERC Consolidator
                Award ID: 724226_cis-CONTROL
                Categories
                Papers

                Genetics
                single-cell transcriptomics,single-cell epigenomics,gene regulatory networks
                Genetics
                single-cell transcriptomics, single-cell epigenomics, gene regulatory networks

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