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EMBO J. 2017 Nov 2;36(21):3232-3249. doi: 10.15252/embj.201796525. Epub 2017 Oct 13.

RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1.

Author information

1
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
2
Institute of Biochemistry, University of Giessen, Giessen, Germany.
3
Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
5
Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
6
Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain.
7
Institute for Genetics, University of Giessen, Giessen, Germany.
8
Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
9
Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
10
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA jrual@umich.edu.

Abstract

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.

KEYWORDS:

RBPJ ; KDM1A; L3MBTL3; Notch signaling

PMID:
29030483
PMCID:
PMC5666606
DOI:
10.15252/embj.201796525
[Indexed for MEDLINE]
Free PMC Article

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