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DNA N4-methylcytosine (4mC) is an important genetic modification and plays crucial roles in differentiation between self and non-self DNA and in controlling DNA replication, cell cycle, and gene-expression levels. Accurate 4mC site identification is fundamental to improve the understanding of 4mC biological functions and mechanisms. Hence, it is necessary to develop in silico approaches for efficient and high-throughput 4mC site identification. Although some bioinformatic tools have been developed in this regard, their prediction accuracy and generalizability require improvement to optimize their usability in practical applications. For this purpose, we here proposed Meta-4mCpred, a meta-predictor for 4mC site prediction. In Meta-4mCpred, we employed a feature representation learning scheme and generated 56 probabilistic features based on four different machine-learning algorithms and seven feature encodings covering diverse sequence information, including compositional, physicochemical, and position-specific information. Subsequently, the probabilistic features were used as an input to support vector machine and developed a final meta-predictor. To the best of our knowledge, this is the first meta-predictor for 4mC site prediction. Cross-validation results show that Meta-4mCpred achieved an overall average accuracy of 84.2% from six different species, which is ∼2%-4% higher than those attainable using the state-of-the-art predictors. Furthermore, Meta-4mCpred achieved an overall average accuracy of 86% on independent datasets evaluation, which is over 4% higher than those yielded by the state-of-the-art predictors. The user-friendly webserver employed to implement the proposed Meta-4mCpred is freely accessible at http://thegleelab.org/Meta-4mCpred.

Meta-4mCpred: A Sequence-Based Meta-Predictor for Accurate DNA 4mC Site Prediction Using Effective Feature Representation