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The second question that comes up is one shared by the community now performing single-cell genomics assays: How do you define a cell type? This question has been thoughtfully explored by Hongkui Zeng, focusing on the complexity of cells in the mammalian brain (Zeng 2022). She not only gives an overview of the many techniques that can be used to address this issue, but she also draws a distinction between cell types and cell states—in other words, how can a canonical cell type exist in several states? Once again, we are brought back to the concept of the epigenetic landscape and a delta of creodes that split off and recombine around the canonical path down the hillside. This reinforces the idea that the original Waddingtonian idea of epigenetics represents a concept that is more relevant today than ever, as we struggle to deal with the complexity of information about cell types and states.

The message from this chapter is that the field of epigenetic studies of hu- man disease has painted itself into a corner through excessive purism. By requiring a model of cellular reprogramming, we have ignored the potential role of cell subtype proportion changes. By requiring mechanisms indepen- dent of DNA sequence variation to mediate effects, we have failed to grasp the opportunity to reveal genetic contributions to phenotypes, while our colleagues in the world of functional variant studies have made excellent progress. By downplaying the role of TFs, we are blinded to the contribution of cell signaling in cellular responses to extrinsic perturbations. In Chapter 5 we tried on for size the new term “cellular genomics” to describe an alter- native way of doing these studies for those uncomfortable still calling this new, more inclusive approach epigenetics. Whatever it is called, it represents a way of merging epigenetics with the work performed by our GWAS and functional variant research colleagues.

With hundreds of PTMs now described for histones, you might imagine that the language that they combine to create is highly complex. However, as has been reviewed by Oliver Rando (Rando 2012), only a tiny proportion of the complexity is used in vivo, with the same combinations of chromatin marks occurring repeatedly in the genome. As Rando puts it (Rando 2012): “At present, an intellectual schism exists between biochemists on one hand, and geneticists and epigenomics researchers on the other. Genome-wide mapping of histone modifications invariably shows that ­ histone modifica- tions occur in groups of multiple highly correlated modifications, demon- strating that the huge potential space of modification combinations is not utilized in vivo.” This lack of diversity argues against the idea that combi- nations of modifications mediate complexity in the regulation of gene ex- pression, although Rando also cites evidence for some readers that bind preferentially when a histone bears a specific combination of PTMs.

A plant epigenetics researcher recounted a story in 2013 about the time she had given a talk at the Gordon Research Conference on Epigenetics, during which she mentioned the role of a transcription factor. After the talk, she was taken aside by one of the more seasoned researchers attending the meeting, who explained to her that “This is an epigenetics meeting. We don’t talk about transcription factors.” This anecdote illustrates how we traditionally dissociated the study of epigenetics from that of transcription factor biology. The silence about TFs in the epigenetics literature is our nonbarking dog. This omission is deliberate, not accidental.

In fact, these authors showed that the association based on DNA methylation outperformed the polygenic risk scores on the same patients, driven substantially by variability due to ancestry and cell type composition estimates derived from DNA methylation data. These results suggest that we may be seeing DNA methylation in action as a molecular sentinel reflect- ing many biological responses by host cells. Many of the laboratory results studied reflected age-associated conditions (e.g., hemoglobin A1C, choles- terol, indices of renal function), raising the intriguing possibility that aging clocks based on DNA methylation may be reflective of the sum of many age-associated
biomarkers. As there is a lot of current discussion about the value of implementing polygenic risk scores as part of population health (Lewis and Vassos 2020), we can anticipate a subsequent wave of interest in the use of methylation risk scores instead, if they continue to show better potential as instruments allowing personalized, precision medicine.

The upshot is a circus of epigenetic diets, epigenetic face creams and other cosmetics, epigenetic yoga and meditation, and even epigenetic antidandruff shampoo, all to be found with a search of the internet. The foundation in evidence for any of these interventions is, at best, extreme- ly weak. The resulting collective eye roll from the broader scientific com- munity demands a response from epigenetics
researchers, who individually may be performing rigorous research but who collectively suffer from what would be described in the world of marketing as “brand damage.”

Book starts with…..

Semantic has become a term of dismissal. That’s just semantics…, I’m not go- ing to enter into a semantic argument with you…, if you want to get seman- tic about it…—you use the word today to suggest that the discussion is not worth your while. It’s as if semantic is taking on the meaning of pedantic, the excessive, inappropriate, and annoying attention to minor details, in Finland described (impolitely) as pilkunnussija or (politely) one who has intimate intercourse with commas.
In telling the story of epigenetics, you must embrace semantics while keeping your inner pedant firmly under control. Today, this rich and fasci- nating avenue of scientific enquiry has not only captured imaginations, it has also captured multiple meanings. Two people discussing epigenetics may think they are talking about the same concept but have completely different and even opposing views of what it means. Someone seeking to construct a hypothesis based on epigenetics can find scraps of evidence from the multi- ple
definitional buckets, building a structure that to the uncritical eye may look solid but lacks the compatible mortises and tenons for stability.