Abstract
It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml, and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb RepressorComplex 2 (PRC2) and LysineDemethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape andrepression of transcription. The demethylase activity of LSD1 is a prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis. Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1173-1183 |
| Number of pages | 11 |
| Journal | Molecular Cancer Research |
| Volume | 15 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2017 |
Fingerprint
ASJC Scopus subject areas
- Molecular Biology
- Oncology
- Cancer Research
Cite this
Notch represses transcription by PRC2 recruitment to the ternary complex. / Han, Xiaoqing; Ranganathan, Prathibha; Tzimas, Christos; Weaver, Kelly L.; Jin, Ke; Astudillo, Luisana; Zhou, Wen; Zhu, Xiaoxia; Li, Bin; Robbins, David J; Capobianco, Anthony J.
In: Molecular Cancer Research, Vol. 15, No. 9, 01.09.2017, p. 1173-1183.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Notch represses transcription by PRC2 recruitment to the ternary complex
AU - Han, Xiaoqing
AU - Ranganathan, Prathibha
AU - Tzimas, Christos
AU - Weaver, Kelly L.
AU - Jin, Ke
AU - Astudillo, Luisana
AU - Zhou, Wen
AU - Zhu, Xiaoxia
AU - Li, Bin
AU - Robbins, David J
AU - Capobianco, Anthony J
PY - 2017/9/1
Y1 - 2017/9/1
N2 - It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml, and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb RepressorComplex 2 (PRC2) and LysineDemethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape andrepression of transcription. The demethylase activity of LSD1 is a prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis. Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response.
AB - It is well established that Notch functions as a transcriptional activator through the formation of a ternary complex that comprises Notch, Maml, and CSL. This ternary complex then serves to recruit additional transcriptional cofactors that link to higher order transcriptional complexes. The mechanistic details of these events remain unclear. This report reveals that the Notch ternary complex can direct the formation of a repressor complex to terminate gene expression of select target genes. Herein, it is demonstrated that p19Arf and Klf4 are transcriptionally repressed in a Notch-dependent manner. Furthermore, results indicate that Notch recruits Polycomb RepressorComplex 2 (PRC2) and LysineDemethylase 1 (KDM1A/LSD1) to these promoters, which leads to changes in the epigenetic landscape andrepression of transcription. The demethylase activity of LSD1 is a prerequisite for Notch-mediated transcriptional repression. In addition, a stable Notch transcriptional repressor complex was identified containing LSD1, PRC2, and the Notch ternary complex. These findings demonstrate a novel function of Notch and provide further insight into the mechanisms of Notch-mediated tumorigenesis. Implications: This study provides rationale for the targeting of epigenetic enzymes to inhibit Notch activity or use in combinatorial therapy to provide a more profound therapeutic response.
UR - http://www.scopus.com/inward/record.url?scp=85028330346&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85028330346&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-17-0241
DO - 10.1158/1541-7786.MCR-17-0241
M3 - Article
C2 - 28584023
AN - SCOPUS:85028330346
VL - 15
SP - 1173
EP - 1183
JO - Molecular Cancer Research
JF - Molecular Cancer Research
SN - 1541-7786
IS - 9
ER -