BRPF3-HUWE1-mediated regulation of MYST2 is required for differentiation and cell-cycle progression in embryonic stem cells

Hye In Cho, Min Seong Kim, Jina Lee, Byong Chul Yoo, Kyung Hee Kim, Kwang Min Choe, Yeun Kyu Jang

Research output: Contribution to journalArticlepeer-review

Abstract

Brpf-histone acetyltransferase (HAT) complexes have important roles in embryonic development and regulating differentiation in ESCs. Among Brpf family, Brpf3 is a scaffold protein of Myst2 histone acetyltransferase complex that plays crucial roles in gene regulation, DNA replication, development as well as maintaining pluripotency in embryonic stem cells (ESCs). However, its biological functions in ESCs are not elucidated. In this study, we find out that Brpf3 protein level is critical for Myst2 stability and E3 ligase Huwe1 functions as a novel negative regulator of Myst2 via ubiquitin-mediated degradation. Importantly, Brpf3 plays an antagonistic role in Huwe1-mediated degradation of Myst2, suggesting that protein–protein interaction between Brpf3 and Myst2 is required for retaining Myst2 stability. Further, Brpf3 overexpression causes the aberrant upregulation of Myst2 protein levels which in turn induces the dysregulated cell-cycle progression and also delay of early embryonic development processes such as embryoid-body formation and lineage commitment of mouse ESCs. The Brpf3 overexpression-induced phenotypes can be reverted by Huwe1 overexpression. Together, these results may provide novel insights into understanding the functions of Brpf3 in proper differentiation as well as cell-cycle progression of ESCs via regulation of Myst2 stability by obstructing Huwe1-mediated ubiquitination. In addition, we suggest that this is a useful report which sheds light on the function of an unknown gene in ESC field.

Original languageEnglish
Pages (from-to)3273-3288
Number of pages16
JournalCell Death and Differentiation
Volume27
Issue number12
DOIs
Publication statusPublished - 2020 Dec

Bibliographical note

Funding Information:
Acknowledgements This work was supported in part by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education [No. 2018R1D1A1B07042777] and partly by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) [No. 2019R1A2C1009907]. In addition, the work was supported in part by Brain Korea 21 (BK21) PLUS program. HIC, MSK., and JL are fellowship awardees by BK21 PLUS program.

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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