Histone code series: H3K27me3 & H3K27ac functions & roles in diseases like DIPG

Histone proteins such as histone H3 are often popping up in science writing and news sometimes includes specific modified forms of H3 including one that we scientists call H3K27me3.

What is in this article

What is H3K27me3? | The histone code | H3K27ac and H3K27me3 function | H3K27 and human disease | References

The goal of today’s post is to explain all about this histone mark and its role in human disease. I will also place it in the larger context of what is called the histone code, the focus of a new blog post series.

What is H3K27me3?

Here is some brief background.

Chromatin is defined as DNA along with an array of proteins including especially histones. What we call the “histone code” includes post-translational modifications of the histones. More on the code in a minute.

H3K27me3 is a specific modified form of histone H3.

These modifications determine how the DNA wrapped around the histones (the chromatin) is structured. In turn, chromatin structure in part defines the activity of specific functional regions in the vicinity such as genes and gene switches.

We sometimes call modified forms of histones by the general term, “marks.” Histones not only come in different types like histone H3 and H4, but also they may have dozens of different modifications on each molecule. This taken together makes up the programming in a sense that tells genes what to do. It’s the histone code.

The histone code

The histone code nomenclature for marks can be a little confusing. Let me explain.

For a specific form of a histone like the H3K27me3 mark of H3, we use the following naming rules.

The “H3” part refers to the main histone that is involved.

In this case it is histone H3.

The K27 portion of the name reflects the residue or amino acid. Here we are talking about residue 27, which is a lysine, represented by the amino acid symbol K. Finally, the “me3” refers to trimethylation of that K residue.

So using this same naming approach acetylated lysine 27 of histone H3 would be H3K27ac.

H3K27ac and H3K27me3 function

When histone H3 is in the H3K27me3 form, it tends to mediate a repressed state transcriptionally.

In other words, genes whose DNA is enriched for this form of H3 tend to be off or have low expression.  Low gene expression means less of the protein is being made. For instance, my lab is interested in a protein called MYC, which has important roles in stem cells but can also drive tumor formation. If the chromatin of the MYC gene is relatively enriched for H3K27me3 forms of histone H3, MYC is likely going to be off or in a low-expression mode.

How is methylation of H3K27 mediated? A protein complex called PRC2 or polycomb repressive complex 2 regulates methylation. If methylation of K27 is absent on a particular histone molecule then it may be acetylated instead, giving us H3K27ac. This is the other main mark of interest in today’s post.

H3K27ac has an opposite kind of function as the methylated form of H3. It tends to be found in more open chromatin. For instance, a gene like MYC that is “on” in certain cells may have relatively more H3K27ac in its promoter. A promoter is kind of like the on-off switch for a gene in terms of its expression. H3K27ac is also found in what are called enhancers, which are akin to long-distance on-off switches for genes. However, we generally think of enhancers as being more of an on-switch. There can also be chromatin domains that are repressors or off switches.

H3K27 and human disease

One of the most well-known diseases linked to H3K27 and its modification status is high-grade childhood glioma. It’s a deadly brain tumor. For example, one form of this type of cancer called diffuse midline glioma often has mutations in H3K27, changing it to a methionine instead. This mutation occurs most often in a variant form of histone H3 called H3.3. My lab studies this mutation, which goes by the name K27M.

We’re hoping to help catalyze new therapies for the kids who get these now almost entirely fatal gliomas.

Interestingly, other mutations are also found in histone H3.3 including in kids’ bone and cartilage tumors and more recently in human neurodevelopmental disorders.

Therefore, H3 and the specific H3.3 variant form are crucial for normal health. We’re studying that too.

Some of our team’s recent work shed fresh light on how the K27M mutant may contribute to glioma.

In a newer paper we reported specific normal neural developmental factors that seem to be coopted by K27M including one called ASCL1. The idea is that when the K27M mutation is present, H3K27me3 is lost at specific genes, leading some like ASCL1 to turn on when they should be off. Our work suggests that ASCL1 then does pro-cancer things. See a network map above of how ASCL1 may contribute to cancer in K27M cells.

I’ll be writing more about histone marks and the code in the future, both in posts about new papers on them and also with new additions to this histone cost blog post series.

References

• Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes, NAR.
• Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity, Nat. Comm.
• Knoepfler Lab paper on K27M.