RUNX3 regulates cell cycle-dependent chromatin dynamics by functioning as a pioneer factor of the restriction-point

• Published in: Nature communications Vol. 10; no. 1; pp. 1897 - 17
• Main Authors: Lee, Jung-Won, Kim, Da-Mi, Jang, Ju-Won, Park, Tae-Geun, Song, Soo-Hyun, Lee, You-Soub, Chi, Xin-Zi, Park, Il Yeong, Hyun, Jin-Won, Ito, Yoshiaki, Bae, Suk-Chul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-04-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 38/15; 38/23; 38/70; 38/91; 631/337; 631/80; 631/80/86/2371; 82/1; 82/111; 82/29; 96/109; 96/2; 96/31; Animals; Butadienes - pharmacology; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell Line, Tumor; Cell Proliferation - drug effects; Chromatin - chemistry; Chromatin - drug effects; Chromatin - metabolism; Chromatin Assembly and Disassembly - drug effects; Chromatin remodeling; Core Binding Factor Alpha 3 Subunit - antagonists & inhibitors; Core Binding Factor Alpha 3 Subunit - genetics; Core Binding Factor Alpha 3 Subunit - metabolism; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 4 - metabolism; Drosophila melanogaster - cytology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Gene Expression Regulation; Genes; HEK293 Cells; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humanities and Social Sciences; Humans; Imidazoles - pharmacology; Loci; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; MAP Kinase Kinase 4 - antagonists & inhibitors; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; Molecular modelling; multidisciplinary; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Nitriles - pharmacology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Piperazines - pharmacology; Polycomb group proteins; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; ras Proteins - genetics; ras Proteins - metabolism; Recruitment; Regulators; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Runx3 protein; S phase; Science; Science (multidisciplinary); Signal Transduction; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09810-w

The cellular decision regarding whether to undergo proliferation or death is made at the restriction (R)-point, which is disrupted in nearly all tumors. The identity of the molecular mechanisms that govern the R-point decision is one of the fundamental issues in cell biology. We found that early after mitogenic stimulation, RUNX3 binds to its target loci, where it opens chromatin structure by sequential recruitment of Trithorax group proteins and cell-cycle regulators to drive cells to the R-point. Soon after, RUNX3 closes these loci by recruiting Polycomb repressor complexes, causing the cell to pass through the R-point toward S phase. If the RAS signal is constitutively activated, RUNX3 inhibits cell cycle progression by maintaining R-point-associated genes in an open structure. Our results identify RUNX3 as a pioneer factor for the R-point and reveal the molecular mechanisms by which appropriate chromatin modifiers are selectively recruited to target loci for appropriate R-point decisions.
The transcription factor RUNX3 plays a key role in the restriction point of cell cycle. Here the authors showed that RUNX3 binds and opens chromatin structure of restriction point associated genes, by sequential recruitment of chromatin remodeling complex, transcription complex and cell cycle regulators.