Network and Evolutionary Analysis of Human Epigenetic Regulators to Unravel Disease Associations.

Shinji Ohsawa,Tomoyoshi Terada,Yoshinori Muto,Toshiaki Umemura

doi:10.3390/genes11121457

Shinji Ohsawa, Tomoyoshi Terada + Show 2 more

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https://doi.org/10.3390/genes11121457

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Journal: Genes	Publication Date: Dec 4, 2020
Citations: 3	License type: CC BY 4.0

Affiliation: Ogaki Women's College, Gifu University, University of Toyama

Abstract

We carried out a system-level analysis of epigenetic regulators (ERs) and detailed the protein–protein interaction (PPI) network characteristics of disease-associated ERs. We found that most diseases associated with ERs can be clustered into two large groups, cancer diseases and developmental diseases. ER genes formed a highly interconnected PPI subnetwork, indicating a high tendency to interact and agglomerate with one another. We used the disease module detection (DIAMOnD) algorithm to expand the PPI subnetworks into a comprehensive cancer disease ER network (CDEN) and developmental disease ER network (DDEN). Using the transcriptome from early mouse developmental stages, we identified the gene co-expression modules significantly enriched for the CDEN and DDEN gene sets, which indicated the stage-dependent roles of ER-related disease genes during early embryonic development. The evolutionary rate and phylogenetic age distribution analysis indicated that the evolution of CDEN and DDEN genes was mostly constrained, and these genes exhibited older evolutionary age. Our analysis of human polymorphism data revealed that genes belonging to DDEN and Seed-DDEN were more likely to show signs of recent positive selection in human history. This finding suggests a potential association between positive selection of ERs and risk of developmental diseases through the mechanism of antagonistic pleiotropy.

Highlights

The term epigenetics refers to heritable traits that are not attributable to changes in the DNA sequence, and this concept has attracted much attention as a potential mechanism underlying the regulation of various cellular processes [1]
To investigate the properties of epigenetic regulators (ERs) associated with human disease, we first compiled a comprehensive set of ERs from two high-quality data sources: the EpiFactors database [9] and the Functional Atlas of Chromatin Epigenetic Regulators (FACER) [8]
A total of 457 diseases were enriched with ER genes at a q-value greater than 0.05, and the number of genes associated with a disease ranged from 2 to as high as 199 for leukemia, with 684 ER genes in all (Supplementary Table S2)

Summary

Introduction

The term epigenetics refers to heritable traits that are not attributable to changes in the DNA sequence, and this concept has attracted much attention as a potential mechanism underlying the regulation of various cellular processes [1]. It is important to note that such epigenetic changes are plastic, which enables cellular reprogramming and response to the environment. This dynamic nature of epigenetics means that epigenetic changes may alter the cellular differentiation and development of an organism, and, if controlled inappropriately, induce various severe disease states [5,6]. Genes 2020, 11, 1457 information about epigenetic regulations and their components in order to fully understand human disorders and their treatment. Extensive researches have been directed towards understanding epigenetic regulatory mechanisms, including various individual components in the regulatory machinery

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