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Mapping Strategy Reveals Unexpected Landmarks in the Pluripotent Chromatin Landscape

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Review of “Insights into Nucleosome Organization in Mouse Embryonic Stem Cells through Chemical Mapping” from Cell by Stuart P. Atkinson

The chromatin landscape present in embryonic stem cells (ESCs) is unique and plays an important role in the maintenance of the pluripotent state. Furthermore, this specialized combination of DNA and histones provides ESCS with the ability to quickly and easily differentiate into any number of different cell types given the appropriate signals. Much of the chromatin landscape arrangement is down to the precise positioning of nucleosomes, and while we have made great advances in our understanding, higher accuracy nucleosomal mapping techniques may be able to tell us more about ESCs and the pluripotent state. 

Researchers working under Ji-Ping Wang and Xiaozhong Wang recently developed a highly-sensitive genome-wide nucleosome mapping approach in yeast [1, 2] and, in a new Cell study, they describe a similar chemical mapping strategy to map nucleosome positions in mouse ESCs [3]. Excitingly, this new advance has encountered a few “unexpected landmarks” in the pluripotent chromatin landscape regarding both nucleosome organization at transcriptional start and stop sites and DNA binding regions pluripotency-associated factors!

Indeed, many of the findings described by Voong et al did not fit the current model, based on micrococcal nuclease digestion followed by high-throughput sequencing (MNase-seq) [4]. The authors encountered a class of “fragile” nucleosomes as regions previously described as nucleosome-depleted regions (NDRs), such as transcription start sites and transcription termination sites. Additional surprises included nucleosome occupancy at target sites for the CCCTC-binding factor (CTCF) insulator protein and the Oct4, Sox2, Nanog, and Klf4 pluripotency factors. Deeper analysis also demonstrated that promoter-proximal nucleosomes contributed to the transcriptional “pausing” of RNA polymerase II at protein-coding genes and that nucleosomes seemed to prefer to occupy exon-intron junction sites.

The discovery of these unexpected landmarks in the pluripotent chromatin landscape may be due to the improved sensitivity of the mapping strategy employed and/or the identification of the less stable fragile nucleosomal units, of which, the authors note, requires further analysis [5]. Looking to the consequences of these findings to our understanding of the pluripotent state, the data also suggests that pluripotency-associated transcription factors may act as “pioneer factors” which can directly bind condensed chromatin and then exert their important influence on transcription.

A brand new map with a few unexpected landmarks; where will it take us next?

References

  1. Brogaard K, Xi L, Wang JP, et al. A map of nucleosome positions in yeast at base-pair resolution. Nature 2012;486:496-501.
  2. Moyle-Heyrman G, Zaichuk T, Xi L, et al. Chemical map of Schizosaccharomyces pombe reveals species-specific features in nucleosome positioning. Proc Natl Acad Sci U S A 2013;110:20158-20163.
  3. Voong LN, Xi L, Sebeson AC, et al. Insights into Nucleosome Organization in Mouse Embryonic Stem Cells through Chemical Mapping. Cell 2016;167:1555-1570 e1515.
  4. Hughes AL and Rando OJ. Mechanisms underlying nucleosome positioning in vivo. Annu Rev Biophys 2014;43:41-63.
  5. Kubik S, Bruzzone MJ, Jacquet P, et al. Nucleosome Stability Distinguishes Two Different Promoter Types at All Protein-Coding Genes in Yeast. Mol Cell 2015;60:422-434.