Live-cell single-molecule dynamics of PcG proteins imposed by the DIPG H3.3K27M mutation

Roubina Tatavosian, Huy Nguyen Duc, Thao Ngoc Huynh, Dong Fang, Benjamin Schmitt, Xiaodong Shi, Yiming Deng, Christopher Phiel, Tingting Yao, Zhiguo Zhang, Haobin Wang and Xiaojun Ren ()
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Roubina Tatavosian: University of Colorado Denver
Huy Nguyen Duc: University of Colorado Denver
Thao Ngoc Huynh: University of Colorado Denver
Dong Fang: Columbia University
Benjamin Schmitt: Colorado State University
Xiaodong Shi: Michigan State University
Yiming Deng: Michigan State University
Christopher Phiel: University of Colorado Denver
Tingting Yao: Colorado State University
Zhiguo Zhang: Columbia University
Haobin Wang: University of Colorado Denver
Xiaojun Ren: University of Colorado Denver

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Over 80% of diffuse intrinsic pontine gliomas (DIPGs) harbor a point mutation in histone H3.3 where lysine 27 is substituted with methionine (H3.3K27M); however, how the mutation affects kinetics and function of PcG proteins remains elusive. We demonstrate that H3.3K27M prolongs the residence time and search time of Ezh2, but has no effect on its fraction bound to chromatin. In contrast, H3.3K27M has no effect on the residence time of Cbx7, but prolongs its search time and decreases its fraction bound to chromatin. We show that increasing expression of Cbx7 inhibits the proliferation of DIPG cells and prolongs its residence time. Our results highlight that the residence time of PcG proteins directly correlates with their functions and the search time of PcG proteins is critical for regulating their genomic occupancy. Together, our data provide mechanisms in which the cancer-causing histone mutation alters the binding and search dynamics of epigenetic complexes.

Date: 2018
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DOI: 10.1038/s41467-018-04455-7

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