Contemporary biology is very much geared (by funding agencies) to applied research, disease-oriented studies and technology. There are not many scientists for whom basic research is of primary interest. Such attitude goes with unselfishness, perseverance, exhausting devotion and incessant work of mind, to be rewarded occasionally by original findings, shaping forthcoming years of research.

Jonathan Widom is (alas – was) this kind of scientist. Imaginative, restless, with a well cultured taste to interesting ideas and explosive results. His passion was DNA and its intricate folding in chromosomes. A series of papers, with R. L. Baldwin, in the 80’s, on the DNA condensation and packaging in viruses, was a spectacular prelude for the rest of Jon’s career (1, 2). Two-three decades later these works still enjoy full recognition – an enviable accomplishment.

From a “simple” spooling of naked DNA Jon turned to an immensely more complex and challenging higher order chromatin structure. His work (with A. Klug) on the 300 Å fiber diffraction gained the same lasting recognition (3). Jon was the first to identify the major problem of all existing detailed models of the chromatin fiber – the necessity of twisting and bending of the linker DNA between the nucleosomes. A whole series of his papers is devoted to that problem (4-6). The nucleosome, a rather static substructure in the higher order approximations and in crystals, started a new life in scientific literature after Jon introduced the notion of DNA breathing in nucleosome. That is, the nucleosomal DNA in its dynamic reality does locally separate from the histone octamers to which it is bound – the more often the closer to the ends of 147-bp long DNA fragment (7-9). This effect was scrutinized highly professionally in several papers, both experimentally and theoretically, with all the elegance characteristic of Jon’s work. The door is open now to the studies on binding transcription regulators to DNA, and accessibility of the binding sites within the nucleosomes (10).

And, of course, the 30-year old question on the DNA sequence determinants of the nucleosome positioning always attracted Jon. Here he solidified his undisputable status of an expert in the chromatin field by a beautiful experiment with randomly synthesized DNA sequences binding to histone octamers (11, 12). What a smashingly simple idea! You just ask the histone octamers themselves what sort of the DNA sequences they like. They turned out to like most the periodical TA dinucleotides (and the TTAA tetranucleotides), which was contrary to the wide-spread belief that the AA and TT dinucleotides are dominant. Thus, one more important sequence element has been added to the reluctantly growing list of the sequence patterns contributing to the positioning of nucleosomes. The exceptionally strongly binding sequence of the TA-periodical “clone 601” became a popular inventory item in studies on the role of nucleosome positioning and strength in gene regulation. In the past five years Jon has taken advantage of the recent progress in the DNA sequencing techniques to address the long-standing problems of the nucleosome organization in the context of chromatin, now at the scale of a whole genome (13, 14). He revealed a critical role of the sequence-dependent ‘mechanics’ of DNA (or DNA ‘deformability’) in guiding the rotational positioning of individual nucleosomes in the chromatin fibril (15). In 2010-2011, many of us enjoyed Jon’s charismatic lectures on the novel chemical approach to the genome-wide mapping of the yeast nucleosomes. One can only wonder how many more exciting experiments and seminal results this gifted scientist, on the top of his productivity, could have generously offered to the world of science ... If not for the heart failure.

Let the name of Jon Widom, the scientist, live long.

References

1. J. Widom and R. L. Baldwin. Cation-induced toroidal condensation of DNA studies with Co3+(NH3)6. J Mol Biol 144(4), 431-53 (1980).
2. J. Widom and R. L. Baldwin. Monomolecular condensation of lambda-DNA induced by cobalt hexamine. Biopolymers 22(6), 1595-620 (1983).
3. J. Widom and A. Klug. Structure of the 300 Å chromatin filament: X-ray diffraction from oriented samples. Cell 43(1), 207-13 (1985).
4. J. Yao, P. T. Lowary, and J. Widom. Direct detection of linker DNA bending in defined-length oligomers of chromatin. Proc Natl Acad Sci U S A 87(19), 7603-7 (1990).
5. J. Yao, P. T. Lowary, and J. Widom. Linker DNA bending induced by the core histones of chromatin. Biochemistry 30(34), 8408-14 (1991).
6. J. Widom. A relationship between the helical twist of DNA and the ordered positioning of nucleosomes in all eukaryotic cells. Proc Natl Acad Sci U S A 89(3), 1095-9 (1992).
7. K. J. Polach and J. Widom. A model for the cooperative binding of eukaryotic regulatory proteins to nucleosomal target sites. J Mol Biol 258(5), 800-12 (1996).
8. J. D. Anderson and J. Widom. Sequence and position-dependence of the equilibrium accessibility of nucleosomal DNA target sites. J Mol Biol 296(4), 979-87 (2000).
9. G. Li and J. Widom. Nucleosomes facilitate their own invasion. Nat Struct Mol Biol 11(8), 763-9 (2004).
10. H. S. Tims, K. Gurunathan, M. Levitus, and J. Widom. Dynamics of nucleosome invasion by DNA binding proteins. J Mol Biol 411(2), 430-48 (2011).
11. P. T. Lowary and J. Widom. New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioning. J Mol Biol 276(1), 19-42 (1998).
12. A. Thåström, L. M. Bingham, and J. Widom. Nucleosomal locations of dominant DNA sequence motifs for histone-DNA interactions and nucleosome positioning. J Mol Biol 338(4), 695-709 (2004).
13. E. Segal, Y. Fondufe-Mittendorf, L. Chen, A. Thåström, Y. Field, I. K. Moore, J. P. Wang, and J. Widom. A genomic code for nucleosome positioning. Nature 442(7104), 772-8 (2006).
14. N. Kaplan, I. K. Moore, Y. Fondufe-Mittendorf, A. J. Gossett, D. Tillo, Y. Field, E. M. LeProust, T. R. Hughes, J. D. Lieb, J. Widom, and E. Segal. The DNA-encoded nucleosome organization of a eukaryotic genome. Nature 458(7236), 362-6 (2009).
15. E. Segal and J. Widom. Poly(dA:dT) tracts: major determinants of nucleosome organization. Curr Opin Struct Biol 19(1), 65-71 (2009).