Histone Replacement / Turnover

November 4, 2007

There were two reports in Science last March on Histone replacement/turnover. These appeared back to back in the March 9 issue (vol 315): Dynamics of Replication-Independent Histone Turnover in Budding Yeast by Dion et. al. (pg 1405-1408 ) and Histone Replacement Marks the Boundaries of cis-Regulatory Domains by Mito et. al. (pg 1408-1411).

The Mito paper (from the Henikoff lab) concerns the replacement of H3 by H3.3 during during transcription and other active processes in Drosophilia. They profile this phenomena using a streptavidin pull-down assay and tilled microarrays. The resulting profile indicate that the homeotic regions (bithorax and antennapedia) show the lowest H3.3/H3 ratio on 3R. A more detailed look at the bithorax region indicates that the peaks of H3.3 correspond well to the boundaries of well studied cis-regulatory regions and the H3.3/H3 ratio peaks over well studied PRE domains … which corresponds with DNaseI hypersensitivity sites. Furthermore, a subset of the H3.3 sites directly correspond with EZ and PSC profiles (polycomb subunits). Meta-gene analysis (summarizing profiles) of top 20% of expressed genes indicates a dip in both H3.3 and H3 at the TSS (likely because of the absence of a nucleosome at this location) and a characteristic peak just inside the gene. The behavior over the gene is reminiscent of Pol II meta-gene profiles. Finally the propose a model of dynamic histone remodeling which constantly displaces nucleosomes and leaves the surrounding DNA accessible by transcription factors and other regulatory proteins. They also claim this cycle may be involved in the establishment of chromatin boundaries.

From this paper, it is apparent that DNaseI hypersensitivity and nucleosome replacement type assays give similar kinds of information. Furthermore, it is implied that this sort of data may help to explain why some very strong transcription factor motifs do not appear bound in ChIP assays for that TF. Finally, if their model is correct (short residence times are in their favor) it paints a much more dynamic picture of regulation than is captured by current analysis methods.

The Dion paper (from the Rando lab) focused on histone turnover in yeast. Yeast contain only a single H3 (a homolog to H3.3 in Drosophilia. Therefore, to study turnover they utilized a strain of yeast with a constitutively expressed Myc-tagged H3 and an inducible Flag-tagged H3. At fixed intervals after turning on the Flag version, they use coarse tiled (~265 bps) microarrays to look at the ratio of the two H3 types. A nice simple model allows them to transform the data into relative rates of turnover — they emphasize that these rates should not be interpreted directly but the ratios are more robust. Therefore they use the ratios to identify hot and cold turnover regions. They find that the hot regions correspond to a subset of transcription factors, chromatin-modulating complexes, and nuclear pore components. The turnover rates in promoters imply that the more common static pictures of histone marks (which have been very popular lately) is inadequate as it can not capture transient states — potentially hiding the informative nature of histone modifications. Finally, they too postulate that turnover may be the key to defining the location of chromatin boundaries … as certain locations turnover too fast to permit the spread of histone marks.

In the last few months I’ve heard Tommy Kaplan, Nir Friedman, and Steve Henikoff all give talks on this work. Both papers are nice pieces of work which together paint a very dynamic picture of histones. Genetic and dynamic studies of histones will be critical to deciphering any instructive role of histone marks in transcriptional control.

Mito, Y., Henikoff, J.G., Henikoff, S. (2007). Histone Replacement Marks the Boundaries of cis-Regulatory Domains. Science, 315(5817), 1408-1411. DOI: 10.1126/science.1134004

Dion, M.F., Kaplan, T., Kim, M., Buratowski, S., Friedman, N., Rando, O.J. (2007). Dynamics of Replication-Independent Histone Turnover in Budding Yeast. Science, 315(5817), 1405-1408. DOI: 10.1126/science.1134053


One Response to “Histone Replacement / Turnover”

  1. […] nucleosomes has to do with histone dynamics. I’ve written before about some elegant work on Histone Turnover, but recently Shivaswamy et. al. took a different approach to the problem. They compared the […]

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