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Associating cellular epigenetic models with human phenotypes

Abstract

Epigenetic association studies have been carried out to test the hypothesis that environmental perturbations trigger cellular reprogramming, with downstream effects on cellular function and phenotypes. There have now been numerous studies of the potential molecular mediators of epigenetic changes by epigenome-wide association studies (EWAS). However, a challenge for the field is the interpretation of the results obtained. We describe a second-generation EWAS approach, which focuses on the possible cellular models of epigenetic perturbations, studied by rigorous analysis and interpretation of genomic data. Thus refocused, epigenetics research aligns with the field of functional genomics to provide insights into environmental and genetic influences on phenotypic variation in humans.

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Figure 1: Epigenetic landscapes of cell reprogramming and cell-fate changes.
Figure 2: Preliminary data from scRNA-seq analysis.
Figure 3: Interpreting the results of a second-generation EWAS.

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Acknowledgements

The authors thank S. Henikoff for sharing his insights and acknowledge his creation of the useful term epi+genetics, as well as R. Satija for advice in single-cell RNA sequencing data analysis.

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Correspondence to Tuuli Lappalainen or John M. Greally.

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Glossary

Canalization

The maintenance of a cell and its progeny within a differentiation lineage. The term refers to the canal-like structures depicted by Waddington in his epigenetic landscape, which he described not as canals but as creodes, a neologism from biblical Greek words meaning 'necessary' and 'path'.

Epigenetic

We define an epigenetic property as that of a cell, mediated by genomic regulators, conferring on the cell the ability to remember a past event.

Epigenome-wide association studies

(EWAS). Studies of the epigenome for nonrandom association of a difference in organization of a genomic regulator, comparing individuals with a phenotype with individuals lacking the phenotype. The epigenome is itself defined as the genome-wide distribution of transcriptional regulators believed to mediate the memory of past cellular events.

Genome-wide association study

(GWAS). A study that looks for association between genetic variation and a high-level trait such as disease or biomarker across individuals, typically scanning millions of genetic variants genome-wide for association signals.

Polycreodism

A systematic variability of cell fate decisions to create a distinctive repertoire of cells in a tissue.

Quantitative trait loci

(QTLs). Loci in the genome at which genetic variation is associated with molecular variation across individuals. For example, individuals with a particular single nucleotide variant have altered expression levels of a gene (eQTL), altered DNA methylation (meQTL; also known as mQTL) or altered chromatin state (chromQTL).

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Lappalainen, T., Greally, J. Associating cellular epigenetic models with human phenotypes. Nat Rev Genet 18, 441–451 (2017). https://doi.org/10.1038/nrg.2017.32

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