Spatial Interplay between Polycomb and Trithorax Complexes Controls Transcriptional Activity in T Lymphocytes

Abstract

Trithorax group (TrxG) and Polycomb group (PcG) proteins are two mutually antagonistic chromatin modifying complexes, however, how they together mediate transcriptional counter-regulation remains unknown. Genome-wide analysis revealed that binding of Ezh2 and menin, central members of the PcG and TrxG complexes, respectively, were reciprocally correlated. Moreover, we identified a developmental change in the positioning of Ezh2 and menin in differentiated T lymphocytes compared to embryonic stem cells. Ezh2-binding upstream and menin-binding downstream of the transcription start site was frequently found at genes with higher transcriptional levels, and Ezh2-binding downstream and menin-binding upstream was found at genes with lower expression in T lymphocytes. Interestingly, of the Ezh2 and menin cooccupied genes, those exhibiting occupancy at the same position displayed greatly enhanced sensitivity to loss of Ezh2. Finally, we also found that different combinations of Ezh2 and menin occupancy were associated with expression of specific functional gene groups important for T cell development. Therefore, spatial cooperative gene regulation by the PcG and TrxG complexes may represent a novel mechanism regulating the transcriptional identity of differentiated cells.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00677-15.

ACKNOWLEDGMENTS

We are grateful to John J. O'Shea, Yuka Kanno, and Golnaz Vahedi for their helpful comments and constructive criticisms in the preparation of the manuscript. We thank Atsushi Iwama and Satoru Miyagi for excellent experimental suggestions.

This study was supported by the Global COE Program (Global Center for Education and Research in Immune System Regulation and Treatment) and by grants from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT Japan; Grants-in-Aid for Scientific Research [S, 26221305; C, 24592083 and 15K08522], for Young Scientists [B, 23790523 and 25860351], and for Scientific Research on Innovative Areas [Genome Science, 221S0002]), by the Ministry of Health, Labor, and Welfare, by the Uehara Memorial Foundation, by the Princess Takamatsu Cancer Research Fund, and by the Takeda Science Foundation. D.J.T. was supported by a Japanese Society for the Promotion of Science postdoctoral fellowship (grant 2109747).