TY - JOUR
T1 - H2A Ubiquitination Alters H3-tail Dynamics on Linker-DNA to Enhance H3K27 Methylation
AU - Ohtomo, Hideaki
AU - Ito, Shinsuke
AU - McKenzie, Nicholas J.
AU - Uckelmann, Michael
AU - Wakamori, Masatoshi
AU - Ehara, Haruhiko
AU - Furukawa, Ayako
AU - Tsunaka, Yasuo
AU - Shibata, Marika
AU - Sekine, Shun ichi
AU - Umehara, Takashi
AU - Davidovich, Chen
AU - Koseki, Haruhiko
AU - Nishimura, Yoshifumi
N1 - Funding Information:
The authors are grateful to Dr. Kyohei Arita for their kind gift of the expression vector that generated the H3 peptide. This work was partly supported by Grants-in-Aid for Scientific Research on an NMR platform [grant number JPMXS0450100021] (to Y.N.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from the Japan Agency for Medical Research, Development (AMED) [Grant Number JP21am0101073 (to Y.N.)] and Grants-in-Aid for Scientific Research (B) [JP20H03388] (to T.U.). H.K. was supported by the Japan Agency for Medical Research and Development (AMED-CREST) (13417643) and Grant-in-Aid for Scientific Research on Innovative Areas (JP19H05745). Sylvia and Charles Viertel Senior Medical Research Fellowship (to C.D.). N.J.M. is the Isabella and Marcus Foundation Charlee Ferrar Scholar and is also supported through an Australian Government Research Training Program (RTP) Scholarship. The cryo-EM experiments were performed at the cryo-EM facility of the RIKEN Center for Biosystems Dynamics Research (Yokohama). The authors declare no competing interests.
Funding Information:
The authors are grateful to Dr. Kyohei Arita for their kind gift of the expression vector that generated the H3 peptide. This work was partly supported by Grants-in-Aid for Scientific Research on an NMR platform [grant number JPMXS0450100021] (to Y.N.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan; Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from the Japan Agency for Medical Research, Development (AMED) [Grant Number JP21am0101073 (to Y.N.)] and Grants-in-Aid for Scientific Research (B) [JP20H03388] (to T.U.). H.K. was supported by the Japan Agency for Medical Research and Development (AMED-CREST) (13417643) and Grant-in-Aid for Scientific Research on Innovative Areas (JP19H05745). Sylvia and Charles Viertel Senior Medical Research Fellowship (to C.D.). N.J.M. is the Isabella and Marcus Foundation Charlee Ferrar Scholar and is also supported through an Australian Government Research Training Program (RTP) Scholarship. The cryo-EM experiments were performed at the cryo-EM facility of the RIKEN Center for Biosystems Dynamics Research (Yokohama).
Publisher Copyright:
© 2022 The Author(s)
PY - 2023/2/28
Y1 - 2023/2/28
N2 - Polycomb repressive complex 1 (PRC1) and PRC2 are responsible for epigenetic gene regulation. PRC1 ubiquitinates histone H2A (H2Aub), which subsequently promotes PRC2 to introduce the H3 lysine 27 tri-methyl (H3K27me3) repressive chromatin mark. Although this mechanism provides a link between the two key transcriptional repressors, PRC1 and PRC2, it is unknown how histone-tail dynamics contribute to this process. Here, we have examined the effect of H2A ubiquitination and linker-DNA on H3-tail dynamics and H3K27 methylation by PRC2. In naïve nucleosomes, the H3-tail dynamically contacts linker DNA in addition to core DNA, and the linker-DNA is as important for H3K27 methylation as H2A ubiquitination. H2A ubiquitination alters contacts between the H3-tail and DNA to improve the methyltransferase activity of the PRC2–AEBP2–JARID2 complex. Collectively, our data support a model in which H2A ubiquitination by PRC1 synergizes with linker-DNA to hold H3 histone tails poised for their methylation by PRC2–AEBP2–JARID2.
AB - Polycomb repressive complex 1 (PRC1) and PRC2 are responsible for epigenetic gene regulation. PRC1 ubiquitinates histone H2A (H2Aub), which subsequently promotes PRC2 to introduce the H3 lysine 27 tri-methyl (H3K27me3) repressive chromatin mark. Although this mechanism provides a link between the two key transcriptional repressors, PRC1 and PRC2, it is unknown how histone-tail dynamics contribute to this process. Here, we have examined the effect of H2A ubiquitination and linker-DNA on H3-tail dynamics and H3K27 methylation by PRC2. In naïve nucleosomes, the H3-tail dynamically contacts linker DNA in addition to core DNA, and the linker-DNA is as important for H3K27 methylation as H2A ubiquitination. H2A ubiquitination alters contacts between the H3-tail and DNA to improve the methyltransferase activity of the PRC2–AEBP2–JARID2 complex. Collectively, our data support a model in which H2A ubiquitination by PRC1 synergizes with linker-DNA to hold H3 histone tails poised for their methylation by PRC2–AEBP2–JARID2.
KW - H2A ubiquitination
KW - H3K27 methylation
KW - histone tail
KW - NMR
KW - polycomb repressive complex
UR - http://www.scopus.com/inward/record.url?scp=85146456822&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2022.167936
DO - 10.1016/j.jmb.2022.167936
M3 - Article
C2 - 36610636
AN - SCOPUS:85146456822
SN - 0022-2836
VL - 435
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 4
M1 - 167936
ER -