Predicting gene expression changes upon epigenomic drug treatment

TL;DR

This study uses machine learning to predict how gene expression changes in response to epigenetic drugs, showing promising accuracy in two cancer cell lines.

Contribution

The paper introduces a machine learning model to predict gene expression changes after HDACi treatment using pre-treatment omics data.

Findings

The model accurately predicted upregulated and downregulated genes after HDACi treatment with an ROC of up to 0.89.

The model trained on one cell line generalized well to another cell line, indicating broad applicability.

Current lack of clinical omics data limits the model's validation in real-world cancer treatment settings.

Abstract

Background

Tumors are characterized by global changes in epigenetic modifications such as DNA methylation and histone modifications that are functionally linked to tumor progression. Accordingly, several drugs targeting the epigenome have been proposed for cancer therapy, notably, histone deacetylase inhibitors (HDACi) such as vorinostat and DNA methyltransferase inhibitors (DNMTi) such as zebularine. However, a fundamental challenge with such approaches is the lack of genomic specificity,
i.e., the transcriptional changes at different genomic loci can be highly variable, thus making it difficult to predict the consequences on the global transcriptome and drug response. For instance, treatment with DNMTi may upregulate the expression of not only a tumor suppressor but also an oncogene, leading to unintended adverse effect.

Methods

Given the pre-treatment transcriptome and epigenomic profile of a sample, we assessed the extent of predictability of locus-specific changes in gene expression upon treatment with HDACi using machine learning.

Results

We found that in two cell lines (HCT116 treated with Largazole at eight doses and RH4 treated with Entinostat at 1µM) where the appropriate data (pre-treatment transcriptome and epigenome as well as post-treatment transcriptome) is available, our model distinguished the post-treatment up
versus downregulated genes with high accuracy (up to ROC of 0.89). Furthermore, a model trained on one cell line is applicable to another cell line suggesting generalizability of the model.

Conclusions

Here we present a first assessment of the predictability of genome-wide transcriptomic changes upon treatment with HDACi. Lack of appropriate omics data from clinical trials of epigenetic drugs currently hampers the assessment of applicability of our approach in clinical setting.

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