Coregulatory effects of multiple histone modifications in key ferroptosis-related genes for lung adenocarcinoma

Abstract

Aim: The present study was designed to investigate the coregulatory effects of multiple histone modifications (HMs) on gene expression in lung adenocarcinoma (LUAD). Materials & methods: Ten histones for LUAD were analyzed using ChIP-seq and RNA-seq data. An innovative computational method is proposed to quantify the coregulatory effects of multiple HMs on gene expression to identify strong coregulatory genes and regions. This method was applied to explore the coregulatory mechanisms of key ferroptosis-related genes in LUAD. Results: Nine strong coregulatory regions were identified for six ferroptosis-related genes with diverse coregulatory patterns (CA9, PGD, CDKN2A, PML, OTUB1 and NFE2L2). Conclusion: This quantitative method could be used to identify important HM coregulatory genes and regions that may be epigenetic regulatory targets in cancers.

Tweetable abstract

A new computational method is proposed to quantify the effects of multiple histone modifications in coregulating gene expression. This work was designed to study the coregulation of ferroptosis-related genes in lung adenocarcinoma and determine key coregulatory genes and regions.

Summary points

• Epigenetic regulators are critical to research on therapeutic targets in cancer. Researchers have reported that histone-modifying enzymes can cause changes in multiple histone modifications (HMs) in research on therapeutic targets. However, quantifying the cooperative effects of multiple HMs in gene expression has not been thoroughly studied.

• A new method to calculate the effect of multiple HMs that coregulate gene expression in lung adenocarcinoma (LUAD) was proposed.

• A coregulation index was defined to quantify the coregulatory effect of HMs on gene expression and the coregulation degree was calculated to identify strong coregulatory regions from various HM coregulatory patterns.

• This coregulatory method was applied to explore the coregulatory mechanisms of key ferroptosis-related genes in LUAD and identified nine strong coregulatory regions of six FRGs: CA9, PGD, CDKN2A, PML, OTUB1 and NFE2L2.

• CA9 and PGD were important regulatory factors of prognosis differences in LUAD patient subsets P and N. Three HM coregulatory patterns and regions of CA9 and PGD were determined, which may represent new directions for improving prognosis for patients with LUAD.

• CDKN2A showed strong single and multiple HM regulatory regions (H3K4me2 and H3K79me2); PML was only strongly regulated by one type of HM (H3K4me2). HMs coregulated CDKN2A and PML to influence the immune infiltrations of Th1, Th2, natural killer T cells, immature dendritic cells and conventional dendritic cells in LUAD.

• Expression variation of PGD is correlated with response to vinorelbine. A better understanding of HM coregulation may promote the efficacy of chemotherapy drugs in the treatment of LUAD.

• This HM coregulation method could be applied to other gene sets besides ferroptosis-related genes. It may help identify therapeutic targets that are coregulated by multiple HMs in cancer.

Keywords: :

• computational method
• coregulation
• drug sensitivity
• ferroptosis
• gene expression
• histone modifications
• lung adenocarcinoma
• tumor microenvironment

Author contributions

Y-C Qi and Q-Z Li were responsible for the study conception and design. Y-C Qi was responsible for the investigation, acquisition of data, methodology and drafting of the manuscript. Y-C Qi, H Bai, S-L Hu and S-J Li were responsible for data analysis. Y-C Qi and Q-Z Li were responsible for the revision of the manuscript. All authors read and approved the final version of the manuscript.

Financial disclosure

This work was supported by the National Natural Science Foundation of China (no. 32160216, 62361047). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Data sharing statement

The data analyzed in this study were obtained from the following resources available in the public domain: Encyclopedia of DNA Elements (ENCODE, www.encodeproject.org) and UCSC Xena (https://xenabrowser.net/datapages/).

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (no. 32160216, 62361047).