Chromatin DANIELA RHODES / MRC LABORATORY OF MOLECULAR BIOLOGY, CAMBRIDGE, UK CAMBRIDGE, BIOLOGY, MOLECULAR OF LABORATORY MRC / RHODES DANIELA Pulling our strings There is much more to DNA than that elegant double helix. Philip Ball explores the twists and tangles of chromatin 50 | Chemistry World | May 2008 www.chemistryworld.org Why isn’t my arm a leg, or my liver read and transcribed into RNA a kidney? Their cells all have the In short – the first step in the conversion same genes. But genetics isn’t just Chromosomes are of genetic information to proteins. about what genes you have – it also made up of a fibrous To understand why some genes depends on how you use them. composite of DNA and are silent while others are actively This crucial aspect of our biological protein called chromatin transcribed – and thus what allows identities has been overshadowed by This coiled network genetically identical cells to become a focus on the identity of our genes, of protein fibres plays differentiated into different tissue and how these differ from those of an important role in types – we need to unravel the other people and other species. But it controlling the activity of packaging. has now become clear that genetics an organism’s genes can’t be fully understood until we Chromatin can be Wound up genes have a better picture, not just of what changed and remodelled In eukaryotic cells, where the is in our genes, but of how they are with chemical labels DNA is housed in a cell nucleus, labelled and packaged. that provide signals for the chromosomes aren’t pure This evolving view of gene enzymes, indicating DNA. About half of their material packaging is quite different from the whether or not genetic is protein: chromosomes are made classical image of genes as stretches material should be up of a fibrous composite of DNA of pristine double-stranded DNA. transcribed into proteins and protein called chromatin. It Our genetic book has been scribbled These modifications, now seems that this structure can all over: there are marginal notes called epigenetic determine the activity of genes, and and sections crossed out. Not only changes, are a way of that it therefore plays as big a role in do these textual changes determine changing the activity of the genetic make-up of organisms what the genetic book says, but they genes without changing as the basic sequence of the genes reveal the book’s history, showing the genes themselves themselves. The chemical nature how its environment has modified of chromatin may hold the key to and shaped its message. understanding how a set of genes Perhaps part of the reason for the creates a complex, multicelled relative neglect of this aspect of gene organism like ourselves – and also function is that it is a tremendously to how this process sometimes goes hard problem, to which the answer awry and leads to conditions such as is likely to be messy. It could be cancer. said that molecular biologists have In 1974, Roger Kornberg, then been in denial ever since Francis working at the UK Medical Research Crick and James Watson discovered Council’s Laboratory of Molecular the structure of DNA in 1953. That Biology (LMB) in Cambridge, beautiful double helix, with its proposed that chromatin is like a genetic information written into the string of beads. The DNA double spiral staircase of paired nucleic- helix, he argued, is acid bases, offers such an elegant looped around picture of the chemical principles of barrel-like life and inheritance that everyone units made fell for it. up of This image of DNA is celebrated proteins in the corridors of biology labs the called world over. But when we come face Chromatin’s proposed histones. to face with DNA in the cell, it’s ‘string of beads’ Each of like meeting a movie star whose structure airbrushed publicity photos don’t look at all like the real thing. You these would barely recognise Crick and barrels is Watson’s perfectly-formed molecule made of two in the tangled, twisted and bent copies each spaghetti that is stuffed inside the of four different nuclei of our cells. histone proteins It may be messy, but the packaging – H2A, H2B, H3 and H4. of DNA into the chromosomes seems Segments of DNA about 146 to have a deep logic to it. These rules base-pairs long are spooled determine how available the DNA is around each histone octamer in for being a double loop. Each of these DNA- histone units is called a nucleosome, and chromatin consists of a succession of nucleosomes linked, by short stretches of DNA, into a flexible chain. There is a fifth histone protein, called H1/H5, attached to the nucleosome at the places where the DNA first makes contact with, and exits from, the protein core. LIBRARY PHOTO SCIENCE / DESIGN LAGUNA www.chemistryworld.org Chemistry World | May 2008 | 51 Chromatin The nucleosomes are themselves packed together to form chromatin fibres about 30nm wide – but no one knows quite how. One idea is that the fibres might be supercoiled into a solenoid, or one-start structure, as happens if you twist the helical cables of old telephones. In this structure, each pair of successive nucleosomes is connected by a bent piece of linking DNA. But it has also been suggested that adjacent nucelosomes along the chain could be connected by straight segments, creating twinned stacks of nucleosome helices – two-start structures (see right). In 2004, Timothy Richmond’s research team at ETH in Zurich, Switzerland, argued that chromatin 1 fibres must have a two-start form. MOZZICONACCI JULIEN But last year, Daniela Rhodes and her colleagues at the LMB challenged coiling, as well as that of the DNA Tangled web: single types of chromatin in the nucleus this idea.2 They chopped up and path around the fibre axis.’ supercoiled or one- of a eukaryotic cell, at least during reconstituted chromatin with It all depends on how many start structure (A) and the interphase period – when it is varying lengths of DNA linking the base pairs there are between one twinned stacks or two- not about to divide. Most is in the nucleosomes – from 10 to 70 base nucleosome and the next, which can start structures (B,C) of form of euchromatin, a fairly open, pairs (bp). They found that, whereas vary in different parts of the genome chromatin fibres gel-like fibrous tangle. The rest is two-start structures should have a and under different conditions. heterochromatin, which is much fibre width that increases gradually In both the centres and the tips of denser and confined to a few small with increasing linker length, in chromosomes, for example, the patches. Because DNA wound fact the fibres fall into two distinct average repeat length is different onto histones and packed tightly classes. For linkers of up to around from the rest. The repeat length also into fibres can’t be accessed by the 40 bp, the fibres have a diameter of seems to change when chromosomes molecular machinery that controls 33nm and contain 11 nucleosomes become compact as a cell prepares transcription of genetic material in every 11nm of length. But with to divide. To accommodate such into RNA, there is a complex array linkers of more than 50 bp, the changes, Mozziconacci thinks that of enzymes involved in unpacking fibres are 44nm wide and have 15 the H1/H5 histone plays the role and repacking (‘remodelling’) nucleosomes per 11nm length. They of an adjustable clip that alters the chromatin, which is vital to the proposed that these results could angle at which the DNA meets and readout of our genes. be understood with yet another exits from the nucleosome core, so It’s tempting to imagine that structure, in which nucleosomes as to make for a tidy fit in the packed- euchromatin is unpacked and in adjacent helical arrays are up fibre. accessible for transcription, while interdigitated. This shape-shifting nature heterochromatin is inactive, The argument isn’t yet settled. could provide a mechanism for like a compressed data file. But Julien Mozziconacci of the controlling gene function. ‘I think it’s not that simple. A lot of the Université Pierre et Marie Curie that the histones evolved so that DNA in euchromatin never gets in Paris, France and his colleagues they can use the helical shape of transcribed – so it’s not obvious why have tried to sort it out by combining DNA to acquire this polymorphism,’ it should be left ‘open’. Conversely, Rhodes’ results with molecular says Mozziconacci. ‘Shuffling chromosomes containing a large modelling.3 They have built of nucleosomes to alter the amount of heterochromatin can computer models of chromatin repeat length might be a way of be transcriptionally active. Some fibres that include every single regulating transcription and other researchers think that euchromatin atom, to see whether the proposed chromosomal processes.’ is actually just a blanket term structures will fit without any atoms It’s still an open question how all that hides structural subtleties of getting in each others’ way. They of this, which stems mostly from ‘Coming face to chromatin we don’t understand. say that chromatin fibres can adopt work on chromatin isolated in test face with DNA ‘How heterochromatin and many different structures, including tubes, carries over to living cells, euchromatin structures differ is the supercoiled solenoid and various but it seems clear that there’s much in the cell is unclear,’ says chemical biologist two-start helices – meaning that more to chromatin structure and like meeting a Michael Grunstein of the University almost all of the theories could be packaging than the 30nm fibres.