Since I started learning about molecular cell biology, I have witnessed an increasing amount of attention to this thing called a "histone code." However, unlike the central dogma of molecular cell biology (i.e. DNA RNA Protein), I still feel very confused about what exactly constitutes the histone code. Is this term code being used rigorously like it is for the central dogma? That is, is there an actual code? If so, what is its alphabet (e.g. GTAC for DNA, GUAC for RNA, the amino acids for proteins)? What kind of words does it encode (e.g. codons for RNA to protein)?

If these things are not known, how do we know it's actually a code then?


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    $\begingroup$ Here is a good resource I found on what all the known histone modifications are, their proposed functions, and literature references. $\endgroup$
    – MattDMo
    Dec 23 '14 at 17:07
  • $\begingroup$ Yes that was helpful. Grazie. $\endgroup$ Dec 23 '14 at 23:22

As already mentioned by Stefan, the "histone" code is not really a universal code; it is restricted to eukaryotic systems and even then, not unambiguous. It is, at present related to two kinds of histone modifications and their correlation with the transcriptional activity at that locus:

  • Methylation
  • Acetylation

Other modifications such as phosphorylation and ubiquitylation also exist but they are not generally considered in this "code".

Acetylation masks the histone's positive charge and thereby loosens the chromatin (DNA wrapped around the histones), which in turn facilitates transcription. Therefore acetylation is almost always activating in the sense of gene expression.

Methylation, on the other hand has different effects. Methylation on Histone-3 at 4th lysine (H3K4) and H3K36 causes activation whereas H3K9 and H3K27 are repressive. There is also some difference between different extent of methylation i.e monomethylation, dimethylation and trimethylation. The effect of methylation is executed by proteins that have domains such as chromodomain and PHD fingers, that identify these modified histones. Sometimes the histone can carry both kinds of methylation marks H3K4me3 and H3K27me3 and these are called bivalents.

Other histones of the octameric nucleosome can also be modified. However as with other kinds of modifications that I mentioned previously they do not seem to be very common and are therefore not generally considered in this "code".

  • $\begingroup$ Is it known that only two kinds of modifications exist or do researchers expect more to be discovered? $\endgroup$ Dec 23 '14 at 8:33
  • $\begingroup$ @StanShunpike as I mentioned that there are other modifications as well but they are either transient (phosphorylation) or used only under specialized conditions (ubiquitylation). Arginine can also be methylated but it is perhaps not as common as lysine methylations. $\endgroup$
    Dec 23 '14 at 8:34

The histone code isn't a sequence of letters like you see in DNA and RNA but rather refers to the pattern of post-translational modification of histones. This is then, by definition, an epigenetic control of gene expression.

Histones are basic DNA binding proteins around which DNA is wound to form chromatin. For transcription to occur, transcription factors and RNA polymerase must bind DNA, which generally cannot happen if DNA is wrapped tightly around histones. DNA must therefore be able to come off from and translocate relative to histones in order to expose bare regions. Based on the level of compaction, chromatin can be generally classified as two types:

  • euchromatin: loosely bound, transcriptionally active
  • heterochromatin: tightly bound, transcriptionally repressed

The state of chromatin compaction is determined by specific post-translational modifications to the residues in the histones' amino-terminal tail. This is the histone code. One commonly talked about and perhaps easiest to understand modifications is acetylation of lysine residues: this is generally considered to activate transcription since it neutralizes the positive charge of the amino acid so the negatively charged DNA isn't attracted as tightly. Phosphorylation of serine or threonine can have a similar effect by introducing negative charges. Other modifications include mono-, di- and trimethylation of lysine and arginine, ubiquitinylation and others that I haven't memorised. Each histone monomer can be modified independently and each has several residues that can be modified; this leads to staggeringly large number of ways in which just a single nucleosome can be modified. Importantly, these modifications can recruit proteins including transcription factors, histone modifiers and chromatin remodellers (which can condense or loosen the chromatin). All of these serve to tightly regulate gene expression. This is an active field of research and what all discovered combinations of modifications do is largely unknown, but certain modifications are often characteristic of active and repressed transcription.

There is a standard convention for conveying histone modifications. For example, if lysine 23 of histone H3 was acetylated, you would write H3K23Ac. For trimethylation of arginine 3 on histone H4, you would write H4R3Me3.


It's not a code in the strict sense of the word. With proteins and nucleic acids you have a strictly defined set of letters and strict rules for them to match one another (note that in some cases atypical base pairing occurs in nucleic acids). The "code" part in histone code is meant to convey the notion that modifications in the histone proteins influence the expression of genetic information. The main mechanisms of histone modification are methylation, acetylation, and ubiquitilation. In a very rough analogy, these would be the "letters" of the histone code (NOTE that this is a very imprecise analogy).

  • $\begingroup$ So it's not a true code in the math-cs sense, but a code in the loose sense of the word code. As in, it stores information that can be likely accessed, recalled and copied. $\endgroup$ Dec 23 '14 at 8:17
  • $\begingroup$ Yes, a "code" in a loose sense. Don't forget to up-vote ;) $\endgroup$
    – Stefan
    Dec 23 '14 at 8:18

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