Format

Send to

Choose Destination
Nat Commun. 2018 May 25;9(1):2080. doi: 10.1038/s41467-018-04455-7.

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

Author information

1
Department of Chemistry, University of Colorado Denver, Denver, CO, 80217-3364, USA.
2
Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
3
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, 80523, USA.
4
Department of Electrical and Computer Engineering, Michigan State University, 428 S. Shaw Lane, East Lansing, MI, 48824, USA.
5
Department of Integrative Biology, University of Colorado Denver, Denver, CO, 80217-3364, USA.
6
Department of Chemistry, University of Colorado Denver, Denver, CO, 80217-3364, USA. xiaojun.ren@ucdenver.edu.

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.

PMID:
29802243
PMCID:
PMC5970213
DOI:
10.1038/s41467-018-04455-7
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center