Single-cell and single-molecule epigenomics uncovers genome regulation at unprecedented resolution

As these GEITP pages have often discussed, any trait (phenotype; e.g. height, eye color, diseases such as schizophrenia and obesity, drug efficacy, or toxicity to an environmental toxicant) reflects contributions of one or many genes (genotype; DNA sequence) and epigenetic effects (DNA-methylation, RNA-interference, histone modifications, chromatin remodeling) plus environmental effects and endogenous influences, and perhaps the gut microbiome. Among the 50-75 trillion cells in the human body, there are ∼210 distinct human cell-types (including those that appear and disappear during development). Contrary to the germline DNA sequence, which is identical in all cells of the body (excluding mutations in specific cells later during life), the human body thus has ∼210 “epigenomes.” And, for the most part, these are DYNAMIC, i.e. changing from minute-to-minute, or from day-to-day.

Large-scale consortia [e.g. Encyclopedia of DNA Elements (ENCODE), National Institutes of Health (NIH) Roadmap Epigenomics Project, & International Human Epigenome Consortium] have applied DNase-I hypersensitivity, chromatin immunoprecipitation (ChIP), and bisulfite sequencing (among others) to characterize chromatin structure, transcription-factor (TF) occupancy, and DNA-methylation — in many cell types and tissues. These genome-wide assays have identified a large diversity of functional regulatory elements and a plethora of chromatin factors that bind these elements. However, these aggregate maps represent averaged signals over populations of cells and thus mask individual-cellular and

-regulatory heterogeneity.

There is now increasing recognition of the importance of cell-to-cell variation within tissues and also measurements of the physical co-occurrence between different chromatin modifications or chromatin regulators at individual loci. Methods for single-cell and single-molecule epigenomic analysis are therefore required to dissect out the mechanisms of gene regulation across the diverse cellular landscape in development and disease.

Advances in molecular biology, microfluidics, and imaging technologies have catalyzed a boom in the number of epigenomic modalities that can be measured at single-cell and single-molecule resolution. Recent reports have described high-throughput single-cell chromatin and DNA-methylation analyses powering epigenomic studies in tens of thousands of cells. Moreover, the surge of technological innovations for single-cell transcriptomics promises to further accelerate the development of single-cell epigenomic technologies. These assays can be used

to characterize cell-types in complex tissues; however, because single-cell transcriptomics is also a widely accessible and robust technology for de novo discovery of cell states, why, then, are single-cell epigenomic studies a worthwhile endeavor?

In the attached article, Authors focus on the unique biology that may be uncovered by single-cell analysis of “the epigenome” in that specific cell. They present a number of motivating concepts unique to single-cell epigenomic analysis (e.g. the unbiased discovery of cis- and trans-regulators and their activity profiles across cell states within complex tissues). Authors also explore how these technologies can be used to answer long-standing questions in cell biology — such as “How do cells choose lineage fates?” and “Is lineage choice first encoded in the epigenome, or in gene expression?”

In addition, authors investigate the biology underlying epigenomic analysis at the single-molecule scale. Lastly, they describe what may be the next generation of single-cell and single-molecule epigenomic tools to advance further our understanding of gene regulation. This Perspective offers a very solid overview of this topic. 🙂


Nat Genet Jan 2019; 51: 19–25

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