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Functional human genes typically exhibit epigenetic conservation

Daniel Rud, Paul Marjoram, Kimberly Siegmund, Darryl Shibata

Abstract
Recent DepMap CRISPR-Cas9 single gene disruptions have identified genes more essential to proliferation in tissue culture. It would be valuable to translate these finding with measurements more practical for human tissues. Here we show that DepMap essential genes and other literature curated functional genes exhibit cell-specific preferential epigenetic conservation when DNA methylation measurements are compared between replicate cell lines and between intestinal crypts from the same individual.

Introduction
Only subsets of genes are expressed in different cell types. It would be valuable to determine which genes are more critical to the survival of specific human cell types. A gene may be considered essential when loss of its function compromises the viability or fitness of its cell [1, 2]. A rigorous approach to determine essentiality is to inactivate a gene and determine subsequent viability

Methods

Experimental design
The objective of this study was to determine if the degree of epigenetic conservation of a gene correlates with its essentiality. Epigenetic conservation requires two measurements of the same cell population separated by sufficient amounts of time for drift to accumulate. Conservation is measured as a pairwise distance between the methylation (beta-values) at a CpG site and varies between 0 and 1.

Materials
The human samples were from excess tissues taken during routine clinical care at the USC Medical Center, with approval by Office for the Protection of Research Subjects at the University of Southern California (HS-18-00043). Specific consent from patients or guardians was waived by the Office for the Protection of Research Subjects at the University of Southern California because the samples were excess tissues obtained in the course of routine clinical care.

Statistical analysis
Statistical Analyses were performed in Excel and R. Significant differences in central tendency were determined with Welch’s unequal variances t-test. Pearson correlation analysis was used to indicate trend of data. Significance level for all tests was set to P = 0.05.

Discussion
Recent systematic CRISPR-Cas9 studies [3] have identified hundreds of essential genes defined by decreased proliferation in culture when the gene is disrupted [1–3]. Here we show that DepMap essential genes also show preferential epigenetic conservation in cell lines and in human tissues.

Citation: Rud D, Marjoram P, Siegmund K, Shibata D (2021) Functional human genes typically exhibit epigenetic conservation. PLoS ONE 16(9): e0253250. https://doi.org/10.1371/journal.pone.0253250

Editor: Anilkumar Gopalakrishnapillai, Alfred I DuPont Hospital for Children, UNITED STATES

Received: May 27, 2021; Accepted: August 8, 2021; Published: September 14, 2021.

Copyright: © 2021 Rud et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The data underlying this study are available on the GEO database (GSE182772).

Funding: This work was supported by NIH Grant U54 U54CA217376 (DS) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

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