Unknown

Dataset Information

0

Predicting gene expression changes upon epigenomic drug treatment.


ABSTRACT:

Background

Tumors are characterized by global changes in epigenetic changes 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 Vorinostatis 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 8 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.

SUBMITTER: Agrawal P 

PROVIDER: S-EPMC10541107 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

altmetric image

Publications

Predicting gene expression changes upon epigenomic drug treatment.

Agrawal Piyush P   Gopalan Vishaka V   Hannenhalli Sridhar S  

bioRxiv : the preprint server for biology 20230723


<h4>Background</h4>Tumors are characterized by global changes in epigenetic changes 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 <i>Vorinostatis</i> and DNA methyltransferase inhibitors (DNMTi) such as <i>Zebularine</i>. However, a fundamental challenge with such approaches is the lack of genomic  ...[more]

Similar Datasets

| PRJNA386477 | ENA
2017-08-09 | GSE98868 | GEO
| S-EPMC5426578 | biostudies-literature
2017-05-16 | PXD005679 | Pride
| S-EPMC8282838 | biostudies-literature
| PRJNA641077 | ENA
2017-02-16 | GSE94943 | GEO
| S-EPMC4623031 | biostudies-literature
2017-08-09 | GSE98867 | GEO
| S-EPMC6287594 | biostudies-literature