Review
Epigenetics: It's Getting Old. Past Meets Future in Paleoepigenetics

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Trends

How are ancient epigenomes reconstructed?

Which epigenetic layers could be reconstructed?

The pros and cons of tissue specificity in paleoepigenetics.

A novel method to infer methylation in unobtainable tissues.

Recent years have witnessed the rise of ancient DNA (aDNA) technology, allowing comparative genomics to be carried out at unprecedented time resolution. While it is relatively straightforward to use aDNA to identify recent genomic changes, it is much less clear how to utilize it to study changes in epigenetic regulation. Here we review recent works demonstrating that highly degraded aDNA still contains sufficient information to allow reconstruction of epigenetic signals, including DNA methylation and nucleosome positioning maps. We discuss challenges arising from the tissue specificity of epigenetics, and show how some of them might in fact turn into advantages. Finally, we introduce a method to infer methylation states in tissues that do not tend to be preserved over time.

Section snippets

Unearthing Epigenetic Layers

The epigenome is viewed today as a collection of regulatory layers that control when, where, and how genes are turned on and off. These layers are passed through cellular or organismal generations and include modifications to the DNA (i.e., DNA methylation) and to the proteins that package it (e.g., histone modifications), as well as regulation by noncoding RNAs (e.g., miRNAs) and changes in the 3D conformation of the genome. While it is still debated which layers are epigenetic and to what

The Rise of Ancient Genomics

Recent years have witnessed the successful high-quality sequencing of two individuals from archaic human groups – a Denisovan at 30× coverage [18], and a Neanderthal at 52× coverage [19]. These works provided the full DNA sequence of these archaic humans, allowing in some cases to associate phenotypes with genetic differences 19, 20. However, as noted earlier, genetics alone cannot explain the full spectrum of phenotypic adaptations. These ancient genomes revealed that the number of fixed amino

Reconstructing Archaic DNA Methylation Maps

DNA methylation, the conversion of cytosine to 5′-methyl-cytosine by DNA methyltransferases, is a fundamental epigenetic mark, involved in the regulation of gene activity. In mammals, methylation usually occurs in the context of a cytosine followed by a guanine (CpG). We are still far from predicting the effect of a local change in methylation on the expression level of a gene. The strongest predictive power is in promoter regions, where hypermethylation is associated with gene silencing [29].

Detecting DMRs

The differentiation of tissues is concomitant with and driven by epigenetic changes. Therefore, the DNA methylation maps of bone cells differ from those of other tissues. As a result, a DMR found when comparing the bones of two individuals would not necessarily exist when comparing these individuals’ brains, for example. However, if a comparison of bone methylation maps revealed a DMR in a region that shows very little variability across tissues, then it is also likely to hold in non-bone

Age Determination

As of today, the biological age of an excavated individual is usually approximated through the analysis of its bone morphology, as the skeleton continues to change in shape, size, and composition from birth to adulthood [62]. In samples other than bone, such as the hair tuft used for the sequencing of the Saqqaq individual [63], the task of age determination is far more challenging. However, recent studies have shown that DNA methylation could be utilized for this task, as the methylation

DNA Packaging

Over the years, the field of epigenetics has paid much attention to DNA methylation, but gene regulation is a multifaceted process, comprising additional important layers. One of the key epigenetic layers is the pattern of DNA packaging; eukaryotic DNA is wrapped around a core octamer of histone proteins which, together with the wrapped DNA, is called the nucleosome. Unwrapped DNA between consecutive nucleosomes is called linker DNA. The nucleosome positions along the genome play an important

Concluding Remarks: One Small Step for a Gene, One Giant Leap for the Organism

Recent evolutionary history is replete with transient, yet dramatic events. For humans, this includes the exodus from Africa, colonization of all climate zones, and the transition to agriculture. Other organisms experienced mass extinctions, drastic climate shifts, and rapid domestication by humans. The ability to infer gene regulation from high-quality DNA of extinct organisms provides a unique opportunity to follow the footsteps of these processes in unprecedented time resolution. In this

Acknowledgment

The work was supported by the Israel Science Foundation FIRST individual grant (ISF 1430/13 to L.C. and E.M.); the Israel Science Foundation (ISF 657/12 to E.M.); and the European Research Council (ERC-281781 to E.M.).

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