RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1.
RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1.
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DOI：
10.15252/embj.201796525
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发表时间：
2017-11-02
期刊：
影响因子：
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通讯作者：
Rual JF
中科院分区：
文献类型：
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作者：
Xu T;Park SS;Giaimo BD;Hall D;Ferrante F;Ho DM;Hori K;Anhezini L;Ertl I;Bartkuhn M;Zhang H;Milon E;Ha K;Conlon KP;Kuick R;Govindarajoo B;Zhang Y;Sun Y;Dou Y;Basrur V;Elenitoba-Johnson KS;Nesvizhskii AI;Ceron J;Lee CY;Borggrefe T;Kovall RA;Rual JF
Notch信号是一种进化上保守的信号转导途径，对后生动物的发育至关重要。配体结合后，Notch胞内结构域（Notch ICD）易位进入细胞核，与转录因子RBPJ（也称为CBF1或CSL）形成复合物，激活Notch靶基因的表达。在缺乏Notch信号的情况下，RBPJ作为转录抑制因子。使用蛋白质组学方法，我们确定了L3MBTL3（也称为MBT1）是一种新的RBPJ相互作用因子。L3MBTL3与NOTCH ICD竞争与RBPJ结合。在缺乏NOTCH ICD的情况下，RBPJ将L3MBTL3和组蛋白去甲基化酶KDM1A（也称为LSD1）招募到NOTCH靶基因的增强子上，导致H3K4me2去甲基化和转录抑制。重要的是，对黑腹果蝇和秀丽隐杆线虫中RBPJ和L3MBTL3同源物的体内分析表明，RBPJ和L3MBTL3之间的功能联系是进化保守的，从而确定了L3MBTL3在后生动物中是Notch信号的通用调节剂。
Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. Upon ligand binding, the Notch intracellular domain (NOTCH ICD) translocates into the nucleus and forms a complex with the transcription factor RBPJ (also known as CBF1 or CSL) to activate expression of Notch target genes. In the absence of a Notch signal, RBPJ acts as a transcriptional repressor. Using a proteomic approach, we identified L3MBTL3 (also known as MBT1) as a novel RBPJ interactor. L3MBTL3 competes with NOTCH ICD for binding to RBPJ. In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and the histone demethylase KDM1A (also known as LSD1) to the enhancers of Notch target genes, leading to H3K4me2 demethylation and to transcriptional repression. Importantly, in vivo analyses of the homologs of RBPJ and L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ and L3MBTL3 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans.