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1. ConnecTF: A platform to integrate transcription factor–gene interactions and validate regulatory networks

   https://doi.org/10.1093/plphys/kiaa012  

   Brooks, Matthew D; Juang, Che-Lun; Katari, Manpreet Singh; Alvarez, José M; Pasquino, Angelo; Shih, Hung-Jui; Huang, Ji; Shanks, Carly; Cirrone, Jacopo; Coruzzi, Gloria M (November 2020, Plant Physiology)

   null (Ed.)

   Abstract Deciphering gene regulatory networks (GRNs) is both a promise and challenge of systems biology. The promise lies in identifying key transcription factors (TFs) that enable an organism to react to changes in its environment. The challenge lies in validating GRNs that involve hundreds of TFs with hundreds of thousands of interactions with their genome-wide targets experimentally determined by high-throughput sequencing. To address this challenge, we developed ConnecTF, a species-independent, web-based platform that integrates genome-wide studies of TF–target binding, TF–target regulation, and other TF-centric omic datasets and uses these to build and refine validated or inferred GRNs. We demonstrate the functionality of ConnecTF by showing how integration within and across TF–target datasets uncovers biological insights. Case study 1 uses integration of TF–target gene regulation and binding datasets to uncover TF mode-of-action and identify potential TF partners for 14 TFs in abscisic acid signaling. Case study 2 demonstrates how genome-wide TF–target data and automated functions in ConnecTF are used in precision/recall analysis and pruning of an inferred GRN for nitrogen signaling. Case study 3 uses ConnecTF to chart a network path from NLP7, a master TF in nitrogen signaling, to direct secondary TF2s and to its indirect targets in a Network Walking approach. The public version of ConnecTF (https://ConnecTF.org) contains 3,738,278 TF–target interactions for 423 TFs in Arabidopsis, 839,210 TF–target interactions for 139 TFs in maize (Zea mays), and 293,094 TF–target interactions for 26 TFs in rice (Oryza sativa). The database and tools in ConnecTF will advance the exploration of GRNs in plant systems biology applications for model and crop species. 

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2. Enhanced Graph Representation Convolution: Effective Inferring Gene Regulatory Network Using Graph Convolution Network with Self-Attention Graph Pooling Layer

   https://doi.org/10.3390/make6030089  

   Alawad, Duaa Mohammad; Katebi, Ataur; Hoque, Md Tamjidul (September 2024, Machine Learning and Knowledge Extraction)

   Studying gene regulatory networks (GRNs) is paramount for unraveling the complexities of biological processes and their associated disorders, such as diabetes, cancer, and Alzheimer’s disease. Recent advancements in computational biology have aimed to enhance the inference of GRNs from gene expression data, a non-trivial task given the networks’ intricate nature. The challenge lies in accurately identifying the myriad interactions among transcription factors and target genes, which govern cellular functions. This research introduces a cutting-edge technique, EGRC (Effective GRN Inference applying Graph Convolution with Self-Attention Graph Pooling), which innovatively conceptualizes GRN reconstruction as a graph classification problem, where the task is to discern the links within subgraphs that encapsulate pairs of nodes. By leveraging Spearman’s correlation, we generate potential subgraphs that bring nonlinear associations between transcription factors and their targets to light. We use mutual information to enhance this, capturing a broader spectrum of gene interactions. Our methodology bifurcates these subgraphs into ‘Positive’ and ‘Negative’ categories. ‘Positive’ subgraphs are those where a transcription factor and its target gene are connected, including interactions among their neighbors. ‘Negative’ subgraphs, conversely, denote pairs without a direct connection. EGRC utilizes dual graph convolution network (GCN) models that exploit node attributes from gene expression profiles and graph embedding techniques to classify these. The performance of EGRC is substantiated by comprehensive evaluations using the DREAM5 datasets. Notably, EGRC attained an AUROC of 0.856 and an AUPR of 0.841 on the E. coli dataset. In contrast, the in silico dataset achieved an AUROC of 0.5058 and an AUPR of 0.958. Furthermore, on the S. cerevisiae dataset, EGRC recorded an AUROC of 0.823 and an AUPR of 0.822. These results underscore the robustness of EGRC in accurately inferring GRNs across various organisms. The advanced performance of EGRC represents a substantial advancement in the field, promising to deepen our comprehension of the intricate biological processes and their implications in both health and disease. 

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3. DeepIMAGER: Deeply Analyzing Gene Regulatory Networks from scRNA-seq Data

   https://doi.org/10.3390/biom14070766  

   Zhou, Xiguo; Pan, Jingyi; Chen, Liang; Zhang, Shaoqiang; Chen, Yong (July 2024, Biomolecules)

   Understanding the dynamics of gene regulatory networks (GRNs) across diverse cell types poses a challenge yet holds immense value in unraveling the molecular mechanisms governing cellular processes. Current computational methods, which rely solely on expression changes from bulk RNA-seq and/or scRNA-seq data, often result in high rates of false positives and low precision. Here, we introduce an advanced computational tool, DeepIMAGER, for inferring cell-specific GRNs through deep learning and data integration. DeepIMAGER employs a supervised approach that transforms the co-expression patterns of gene pairs into image-like representations and leverages transcription factor (TF) binding information for model training. It is trained using comprehensive datasets that encompass scRNA-seq profiles and ChIP-seq data, capturing TF-gene pair information across various cell types. Comprehensive validations on six cell lines show DeepIMAGER exhibits superior performance in ten popular GRN inference tools and has remarkable robustness against dropout-zero events. DeepIMAGER was applied to scRNA-seq datasets of multiple myeloma (MM) and detected potential GRNs for TFs of RORC, MITF, and FOXD2 in MM dendritic cells. This technical innovation, combined with its capability to accurately decode GRNs from scRNA-seq, establishes DeepIMAGER as a valuable tool for unraveling complex regulatory networks in various cell types. 

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4. Engineering activatable promoters for scalable and multi-input CRISPRa/i circuits

   https://doi.org/10.1073/pnas.2220358120  

   Alba_Burbano, Diego; Cardiff, Ryan_A L; Tickman, Benjamin I; Kiattisewee, Cholpisit; Maranas, Cassandra J; Zalatan, Jesse G; Carothers, James M (July 2023, Proceedings of the National Academy of Sciences)

   Dynamic, multi-input gene regulatory networks (GRNs) are ubiquitous in nature. Multilayer CRISPR-based genetic circuits hold great promise for building GRNs akin to those found in naturally occurring biological systems. We develop an approach for creating high-performing activatable promoters that can be assembled into deep, wide, and multi-input CRISPR-activation and -interference (CRISPRa/i) GRNs. By integrating sequence-based design and in vivo screening, we engineer activatable promoters that achieve up to 1,000-fold dynamic range in anEscherichia coli-based cell-free system. These components enable CRISPRa GRNs that are six layers deep and four branches wide. We show the generalizability of the promoter engineering workflow by improving the dynamic range of the light-dependent EL222 optogenetic system from 6-fold to 34-fold. Additionally, high dynamic range promoters enable CRISPRa systems mediated by small molecules and protein–protein interactions. We apply these tools to build input-responsive CRISPRa/i GRNs, including feedback loops, logic gates, multilayer cascades, and dynamic pulse modulators. Our work provides a generalizable approach for the design of high dynamic range activatable promoters and enables classes of gene regulatory functions in cell-free systems. 

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5. The biology of time: dynamic responses of cell types to developmental, circadian and environmental cues

   https://doi.org/10.1111/tpj.15589  

   Swift, Joseph; Greenham, Kathleen; Ecker, Joseph R.; Coruzzi, Gloria M.; Robertson McClung, C. (December 2021, The Plant Journal)

   SUMMARY As sessile organisms, plants are finely tuned to respond dynamically to developmental, circadian and environmental cues. Genome‐wide studies investigating these types of cues have uncovered the intrinsically different ways they can impact gene expression over time. Recent advances in single‐cell sequencing and time‐based bioinformatic algorithms are now beginning to reveal the dynamics of these time‐based responses within individual cells and plant tissues. Here, we review what these techniques have revealed about the spatiotemporal nature of gene regulation, paying particular attention to the three distinct ways in which plant tissues are time sensitive. (i) First, we discuss how studying plant cell identity can reveal developmental trajectories hidden in pseudotime. (ii) Next, we present evidence that indicates that plant cell types keep their own local time through tissue‐specific regulation of the circadian clock. (iii) Finally, we review what determines the speed of environmental signaling responses, and how they can be contingent on developmental and circadian time. By these means, this review sheds light on how these different scales of time‐based responses can act with tissue and cell‐type specificity to elicit changes in whole plant systems. 

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