Insight Into the Inheritance of Epigenetic Marks

An individual’s DNA contains the sequence of nucleotide bases that provide instructions for how every cell in their body is to develop and differentiate. When DNA is read, its instructions are followed to guide the development of cells, allowing genes to be “expressed”. Scientists are actively working to map out the cellular signaling pathways that determine how DNA is differentially expressed, as well as the things that could go wrong, which could ultimately end up in disease.

But there’s an added layer of control at play that extends beyond manipulating the actual code of DNA. Chromosomes comprised of the DNA sequence are wrapped around histones, or proteins that act as something between packaging and structure. The extent of “tightness” with which DNA is wrapped around these histones determines how accessible the DNA is to the cellular machinery that expresses it, mainly though the binding of specific proteins. 

Epigenetics studies the modifications to DNA that controls how accessible it is to cellular machiner, all while the underlying sequence is unchanged. Chemical modifications can be made to the histones that affect how wound (or unwound) the DNA is. The most common modification is DNA methylation, where a methyl group is added to the cytosine base of the DNA backbone, which ultimately alters how the sequence is read.

One question that plagues researchers is: do these modifications get passed down during cell division and, if so, how?

Axel Imhof’s team at Ludwig-Maximilians-Universitat-Munchen collaborated with the Helmholtz Zentrum Munchen as well as a Danish team to use modelling methods alongside experiments to clarify how epigenetic marks are established after cells divide.

Specifically, they looked at the lysines at positions 27 (K27me) and 36 (K36me) on histone H3. K27me is usually associated with inactive genes, while K36me is usually associated with active genes. Imhof’s team labelled new histones with non-radioactive isotopes, and the old histones with radioactive ones.

After cell division, researchers could spot where the histones landed. From there, they used more detailed theoretical modeling to further map out patterns—which turned out to be far more complex than originally anticipated. It turns out that up to three methyl groups could attach at each of the lysine locations under study, which resulted in 16 total isoforms to consider.

What were the findings?

First, this research team established a model that can be replicated and applied to other methylation sites, as a way to explore patterns of methylation across generations. This is a powerful outcome for epigenetics research, opening the door for further studies.

One key finding was that the presence of K27me on histone 3 stimulated the establishment of methylation on the newly generated chromatin. This follows a “read-write” mechanism, just like data storage in computers, where inputs lead to the access of data, which can then be handled or even edited; the methylation on the old chromatin is read, and placed onto the new one. This was supported by data that showed that the lack of K27me on the old histone reduced the rate of methylation on the new (or “de novo”) K27.

The other key finding was that K27me and K36me act opposite to each other, which aligns with a lot of existing studies both in vivo and in vitro; however, this relationship is somewhat complex. Since there’s no evidence that K27 methylation directly regulates K365 methyltransferases, it seems as though this happens indirectly via chromatin remodeling or other changes that impact the affinity between the methylation site and the enzyme that would carry out this methylation.

What’s next?

Imhof notes, “…A lot of work is currently going into the development of ‘epidrugs’ that could modulate the activity of these enzymes.” Being able to quickly identify these epigenetic changes and potentially even modulate them could represent huge potential for disease intervention. This seems to be particularly promising within the realm of cancer research, as tumor cells are known to use mutant enzymes to generate new modifications that rapidly increase the rates of cellular division.

Source: Alabert C. et al.(2020) Domain Model Explains Propagation Dynamics and Stability of Histone H3K27 and H3K36 Methylation Landscapes. Cell Reports, 30 (4) 1223-1234.

Reference:  Ludwig-Maximilians-Universitat-Munchen “Inheritance of epigenetic marks” LMU News 10 Feb. 2020. Web.