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Individual cells, a new epigenomic target

All somatic cells of a body have the same genome. But each of them can present a different gene expression profile depending on the epigenetic marks that, acting as molecular switches, activate or deactivate these sequences. These regulatory systems, globally known as the epigenome, include the chemical modification of the genetic fragments and the histones, or changes in the accessibility and make-up of the DNA.

Although the current techniques in epigenetics focus on the analysis of large cell populations, the arrival of individual cell transcriptomics has accelerated the application of these methods to study what happens inside a single cell, which is also beginning to occur at the epigenetic level. According to a study published in Nature Reviews Genetics, the purpose of these new technologies, geared to capture DNA methylation, chromatin accessibility, histone modifications, chromosome conformation and replication dynamics, is to discover more about cellular plasticity and diversity.

DNA methylation
Source: Christoph Bock - Max Planck Institute for Informatics (Wikimedia)

Answering many of biology's deepest questions depends on understanding what is happening at the individual level in a single cell. As opposed to what occurs in major cell populations and even tissues, exploring the epigenetic changes that occur in individual cells will empower us to refine our knowledge on embryonic development  or serious pathologies such as cancer. With these advancements, as suggested in an article published in Science, researchers will be able to determine how transcriptional heterogeneity among cells relates with epigenetic heterogeneity, or if the changes in transcription occur before or after the epigenetic variations when cells modify their purpose or function, among other matters.

Some of the emerging techniques to map the epigenome of an individual cell are the well-known bisulfite sequencing which enables the identification of methylated cytosines, chIP-Seq technology, to determine the modification of histones, or others, such as NOME-seq, FAIRE-seq and MNase-seq, all of which are used to study chromatin structure. In the various cases, as described in a study published in Genome Biology, “a single cell is first isolated by means of droplet encapsulation, manual manipulation, fluorescence-activated cell sorting (FACS) or microfluidic processing”, to later proceed with the various other techniques required for research.


Source: Stephen J. Clark et al. - Genome Biology (Wikimedia)

 

Nevertheless, at the present time, the technologies available to study the epigenetic marks in individual cells still face limitations. Researcher Estephany Ferrufino mentions as some of the most relevant problems “low mappability rates, limited capture rates, and high levels of PCR duplicates.” For example, one of the most notable challenges of the bisulfite technique is its inability to obtain complete coverage of the genome methylation of a single cell. At present, the protocols designed have only achieved coverages of nearly 40%, far from the goals of the scientific community.

The omics techniques that will give scientists the capacity to better understand an individual cell's epigenetic switches are still in the earliest stages. If things evolve as foreseen, the progress being made in these methods will be the key to identifying "individual signatures" in the epigenome to determine, for example in the clinical area, a precancerous status of specific cells. Landmarks like this are still distant, but when reached, they will open the doors to early diagnosis and treatment of individual cells. As concerns basic research, such studies will also help us better understand the identity and function of every cell and understand the different physiological and pathological states of interest.