Journal Article

Accurate and highly interpretable prediction of gene expression from histone modifications

Masseroli, Marco, Leone, Michele, Frasca, Fabrizio, Matteucci, Matteo, Morelli, Marco J.

2022

Overview

Background Histone Mark Modifications (HMs) are crucial actors in gene regulation, as they actively remodel chromatin to modulate transcriptional activity: aberrant combinatorial patterns of HMs have been connected with several diseases, including cancer. HMs are, however, reversible modifications: understanding their role in disease would allow the design of ‘epigenetic drugs’ for specific, non-invasive treatments. Standard statistical techniques were not entirely successful in extracting representative features from raw HM signals over gene locations. On the other hand, deep learning approaches allow for effective automatic feature extraction, but at the expense of model interpretation. Results Here, we propose ShallowChrome, a novel computational pipeline to model transcriptional regulation via HMs in both an accurate and interpretable way. We attain state-of-the-art results on the binary classification of gene transcriptional states over 56 cell-types from the REMC database, largely outperforming recent deep learning approaches. We interpret our models by extracting insightful gene-specific regulative patterns, and we analyse them for the specific case of the PAX5 gene over three differentiated blood cell lines. Finally, we compare the patterns we obtained with the characteristic emission patterns of ChromHMM, and show that ShallowChrome is able to coherently rank groups of chromatin states w.r.t. their transcriptional activity. Conclusions In this work we demonstrate that it is possible to model HM-modulated gene expression regulation in a highly accurate, yet interpretable way. Our feature extraction algorithm leverages on data downstream the identification of enriched regions to retrieve gene-wise, statistically significant and dynamically located features for each HM. These features are highly predictive of gene transcriptional state, and allow for accurate modeling by computationally efficient logistic regression models. These models allow a direct inspection and a rigorous interpretation, helping to formulate quantifiable hypotheses.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Algorithms / Analysis / Bioinformatics / Biomedical and Life Sciences / Blood cells / Cell differentiation / Chromatin / Classification / Combinatorial analysis / Computational Biology/Bioinformatics / Computational linguistics / Computer Appl. in Life Sciences / Computer applications / Deep learning / Design modifications / Drug development / Epigenetic inheritance / Epigenetics / Experiments / Feature extraction / Gene Expression / Gene expression regulation / Gene regulation / Genomes / Histone Code / Histone modifications / Histones / Histones - metabolism / Inspection / Interpretability / Language processing / Life Sciences / Machine learning / Methods / Microarrays / Natural language interfaces / Pax5 gene / Pax5 protein / Protein Processing, Post-Translational / Regression analysis / Regression models / Statistical analysis / Testing / Transcription