Dr. Jerry Workman discusses the questions surrounding the preservation of histone marks, and the balance between histone turnover and transgenerational inheritance.

The Dynamic Histone Code

I think one of the most exciting things for me that’s being approached in the field more recently is how are histone marks preserved? We talk about these things carrying on through generations and certainly through many generations of cells and stuff. And it’s become increasingly apparent that histones are very dynamic. They’re turning over all the time. So if you put marks on histones that are supposed to carry information, how do you keep it there when you keep exchanging histones with soluble pools?

So some of our work and our colleagues has to do with elongation of transcription by RNA polymerase. And it’s impossible for RNA polymerase to go through DNA sequences that are contained in nucleosomes. It’s just not physically possible because the DNA is wrapped around the nucleosome, but has to go through the middle of a polymerase.

So if the polymerase knocks off all the histones, then you’ve lost all the information on those histones. And yet somehow, that stuff is retained. And so there’s a combination of histone chaperones and modifications, et cetera, that somehow preserve and reuse the original histones to remake nucleosomes behind the polymerase. But that’s a very complicated process. And trying to understand that I think will not only tell us a lot about transcription elongation, but other processes where you have chromatin remodeling and things turning over, whether it be DNA repair or DNA replication or whatever.

Evolving Views on Nucleosomes and Transcription

And so a lot of these things I think are breaking down our old standing paradigms. I know when I entered the field the idea was that– well, the first idea was that nucleosomes weren’t going to be important because bacteria regulate transcription and they don’t have nucleosomes. It turns out they probably do have some kind of chromatin that’s interesting.

And then when we and others showed that nucleosomes inhibit transcription, then it was like well, they’re too stable. They’re much more stable than any other protein DNA and so how could they possibly be dealt with? But now with all the things that act on histones all the time, histone chaperones, chromatin remodelers, whatever, it seems to be that the bigger problem is keeping them stable because the cell wants to turn them over. And the nucleosome assembly machinery is basically just like histone pressure.

So there’s like pressure. Any DNA that becomes open in the nucleus gets nucleosomes put on it. But you have to make it open to get polymerase through and to do other things like that. And so how do you keep it from acquiring new histones and keep the old ones that have the epigenetic marks that may be important and contain various information?

“…it’s become increasingly apparent that histones are very dynamic. They’re turning over all the time. So if you put marks on histones that are supposed to carry information, how do you keep it there when you keep exchanging histones with soluble pools?”

And so I think that’s a very fascinating process right now. As I said, we study it with regard to transcription elongation. But I think that will be true with just about any other genomic process. And it probably has more to do with positive feedback than anything.

There’s a number of examples of enzymes that make a modification, recognize and bind to those modifications, either by themselves or through other subunits of the same complex. And so in principle, they can continuously reinforce a modification on nucleosomes within a given domain, where we’ve seen this for histone methyltransferases, histone acetyltransferases, or whatever. And so the histone mark is probably only really part of the epigenetic marks that they might contribute to. But it’s a combination of the protein complexes that do the modification, as well as the modified histones themselves.