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      Prediction of Transcription Factor Binding Sites Using a Combined Deep Learning Approach

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          Abstract

          In the process of regulating gene expression and evolution, such as DNA replication and mRNA transcription, the binding of transcription factors (TFs) to TF binding sites (TFBS) plays a vital role. Precisely modeling the specificity of genes and searching for TFBS are helpful to explore the mechanism of cell expression. In recent years, computational and deep learning methods searching for TFBS have become an active field of research. However, existing methods generally cannot meet high performance and interpretability simultaneously. Here, we develop an accurate and interpretable attention-based hybrid approach, DeepARC, that combines a convolutional neural network (CNN) and recurrent neural network (RNN) to predict TFBS. DeepARC employs a positional embedding method to extract the hidden embedding from DNA sequences, including the positional information from OneHot encoding and the distributed embedding from DNA2Vec. DeepARC feeds the positional embedding of the DNA sequence into a CNN-BiLSTM-Attention-based framework to complete the task of finding the motif. Taking advantage of the attention mechanism, DeepARC can gain greater access to valuable information about the motif and bring interpretability to the work of searching for motifs through the attention weight graph. Moreover, DeepARC achieves promising performances with an average area under the receiver operating characteristic curve (AUC) score of 0.908 on five cell lines (A549, GM12878, Hep-G2, H1-hESC, and Hela) in the benchmark dataset. We also compare the positional embedding with OneHot and DNA2Vec and gain a competitive advantage.

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          Most cited references34

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          Long Short-Term Memory

          Learning to store information over extended time intervals by recurrent backpropagation takes a very long time, mostly because of insufficient, decaying error backflow. We briefly review Hochreiter's (1991) analysis of this problem, then address it by introducing a novel, efficient, gradient-based method called long short-term memory (LSTM). Truncating the gradient where this does not do harm, LSTM can learn to bridge minimal time lags in excess of 1000 discrete-time steps by enforcing constant error flow through constant error carousels within special units. Multiplicative gate units learn to open and close access to the constant error flow. LSTM is local in space and time; its computational complexity per time step and weight is O(1). Our experiments with artificial data involve local, distributed, real-valued, and noisy pattern representations. In comparisons with real-time recurrent learning, back propagation through time, recurrent cascade correlation, Elman nets, and neural sequence chunking, LSTM leads to many more successful runs, and learns much faster. LSTM also solves complex, artificial long-time-lag tasks that have never been solved by previous recurrent network algorithms.
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            An Integrated Encyclopedia of DNA Elements in the Human Genome

            Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
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              MEME Suite: tools for motif discovery and searching

              The MEME Suite web server provides a unified portal for online discovery and analysis of sequence motifs representing features such as DNA binding sites and protein interaction domains. The popular MEME motif discovery algorithm is now complemented by the GLAM2 algorithm which allows discovery of motifs containing gaps. Three sequence scanning algorithms—MAST, FIMO and GLAM2SCAN—allow scanning numerous DNA and protein sequence databases for motifs discovered by MEME and GLAM2. Transcription factor motifs (including those discovered using MEME) can be compared with motifs in many popular motif databases using the motif database scanning algorithm Tomtom. Transcription factor motifs can be further analyzed for putative function by association with Gene Ontology (GO) terms using the motif-GO term association tool GOMO. MEME output now contains sequence LOGOS for each discovered motif, as well as buttons to allow motifs to be conveniently submitted to the sequence and motif database scanning algorithms (MAST, FIMO and Tomtom), or to GOMO, for further analysis. GLAM2 output similarly contains buttons for further analysis using GLAM2SCAN and for rerunning GLAM2 with different parameters. All of the motif-based tools are now implemented as web services via Opal. Source code, binaries and a web server are freely available for noncommercial use at http://meme.nbcr.net.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                03 June 2022
                2022
                : 12
                : 893520
                Affiliations
                [1] School of Computer Science and Engineering, Central South University , Changsha, China
                Author notes

                Edited by: Rui Guo, Harvard Medical School, United States

                Reviewed by: Yongchun Zuo, Inner Mongolia University, China; Wei Chen, North China University of Science and Technology, China

                *Correspondence: Lei Deng, leideng@ 123456csu.edu.cn

                †These authors have contributed equally to this work

                This article was submitted to Cancer Genetics, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2022.893520
                9204005
                9a5c4d13-41f0-4e1f-8b01-b6dd93f6b0ff
                Copyright © 2022 Cao, Liu, Chen and Deng

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 March 2022
                : 11 April 2022
                Page count
                Figures: 5, Tables: 4, Equations: 15, References: 34, Pages: 10, Words: 5405
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                transcription factor binding sites,attention mechanism,positional embedding,deep learning,dna

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