Histones Require a Towtruck With a Winch

Motorized remodelers adjust and open up chromatin for gene expression.

Wouldn't it be nice if, on a stop-and-go congested highway, you could just plow through all the obstructing cars and go where you want? That is what polymerases get to do on our DNA, once they are set in motion. They plow right through chromatin, histones, DNA-binding transcription regulators, and everything else in their way. But getting them to that point is a different matter. Origins of replication need to be carefully cleared and set up. Promoters of genes need to be activated by the convergence of enhancer-binding proteins, promoter-binding proteins, and mediators of various kinds to get that RNA polymerase set on its path. And that is not so easy in a chromatin environment where the DNA is almost all covered by something, principally histones that wind up our DNA in tight little 146 base pair loops.

A basic schematic of nucleosome cores (yellow), composed of histone proteins, and how they wind up DNA and pack with each other.

So a class of "chromatin remodelers" have evolved that move histones around, and exchange histones in a way that facilitates transcription. It became apparent a couple of decades ago that regions of active transcription have altered histone composition, H2A.z/H3.3 instead of the regular H2A and H3 histones. These histones are looser, allowing regulatory proteins better access to the DNA as well as easing the passage of the polymerases. But how do they get there? It has also gradually become apparent that regulatory proteins come in different types, with some "pioneer" regulators able to bind in the midst of packed chromatin. These in turn recruit additional regulators, including enzymes that loosen up histones by chemically altering them with methyl, acetyl, and other modifications, and remodeling enzymes that push histones around, revealing DNA where other regulators can bind, and popping out conventional histones for more weakly-binding ones.

A few recent papers revealed the structure of a few of these remodeling enzymes, and compare them between yeast cells and human cells. There are a variety of these machines, which specialize things like nudging nucleosomes into regular spacing, or evicting/moving nucleosomes from particular regions, such as near transcription regulators, or exchanging nucleosomes in active regions. It is the latter that is being studied here. In yeast, this SWI/SNF family remodeler comes in two parts, NuA4, which is a histone acetylase, and SWR1, which uses ATP to winch out H2A and replace it with H2A.z. These protein complexes cooperate with each other and have related effects in opening local chromatin to be more transcription competent. In humans, these complexes are combined into one super-complex, TIP60-C, which weighs in at 1.8 million daltons, a dalton being the mass of one hydrogen atom. One can appreciate here, as in so many other details of biology, the nature of evolution- the tension between conservation and change.

Chromatin remodelers from yeast (top) and human (bottom). SWI/SNF is on the left, and RSC is on the right. Both of these remodelers have wide capabilities of moving or replacing nucleosomes. DNA is in orange, and the histone is at top, within the DNA coils. See text for further description.

At top are the structures of two yeast remodelers, SWI/SNF and RSC. At bottom are structures of the corresponding human remodelers, BAF and PBAF. One can appreciate how similar they are in overview, while being very different in detail. All of these remodelers function in detailed transcriptional control in collaboration with other regulators. The orange structure is the DNA wrapped around a nucleosome, while the large blobs at the bottom of these structures are relatively loose regions where they interact with other transcription regulators, which recruit them to the proper locations. The ATP-driven motor is shown at the top in green, and grabs tightly, with two RecA domains (that is to say, with two hands) to bits of the DNA circling the nucleosome. Given that the whole apparatus is anchored to the histone and other nearby structures, this enables the motor to pull on the DNA. It is pretty slow, moving only 1 or 2 base pairs per ATP used, but with enough copies (of these motors) and time, great things can be done. The structure in (b) indicates where the DNA enters (top) and where it gets pulled towards (bottom) as the motor works. This action can nudge the histone to some new location, relative to the DNA. Alternately, with other forms of anchoring, it can also pop the histone entirely off the DNA, and, since this large protein complex can bind alternative histone complexes, can bring in a new histone for exchange.  

Downloadable animation of nucleosome movement (source). 

Downloadable animation of overall assembly and nucleosome spacing activity (source).

So in short, what we have here is a DNA winch, which in various configurations can adjust, evict, or exchange nucleosomes, as directed by various signals. One signal is the sequence of the DNA itself, another is the standard spacing between chromosomes that is set by some of these motors that have a suitably sized extension, extending out to touch the next histone, and establishes the default nucleosome pattern, genome-wide. But more significant are the various pioneer regulators and histone modifiers that direct these motors to specific areas to reshape the local chromatin to control gene expression. Here is where the regulatory action is, and these proteins have been found to be determinants for cancer progression, and indeed are targets for some investigational anti-cancer drugs.

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