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NOTCH1 nuclear interactome reveals key regulators of its transcriptional activity and oncogenic function.

Abstract：

:Activating mutations in NOTCH1, an essential regulator of T cell development, are frequently found in human T cell acute lymphoblastic leukemia (T-ALL). Despite important advances in our understanding of Notch signal transduction, the regulation of Notch functions in the nucleus remains unclear. Using immunoaffinity purification, we identified NOTCH1 nuclear partners in T-ALL cells and showed that, beyond the well-characterized core activation complex (ICN1-CSL-MAML1), NOTCH1 assembles a multifunctional complex containing the transcription coactivator AF4p12, the PBAF nucleosome remodeling complex, and the histone demethylases LSD1 and PHF8 acting through their demethylase activity to promote epigenetic modifications at Notch-target genes. Remarkably, LSD1 functions as a corepressor when associated with CSL-repressor complex and as a NOTCH1 coactivator upon Notch activation. Our work provides new insights into the molecular mechanisms that govern Notch transcriptional activity and represents glimpse into NOTCH1 interaction landscape, which will help in deciphering mechanisms of NOTCH1 functions and regulation.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Yatim A,Benne C,Sobhian B,Laurent-Chabalier S,Deas O,Judde JG,Lelievre JD,Levy Y,Benkirane M

doi

10.1016/j.molcel.2012.08.022

subject

Has Abstract

pub_date

2012-11-09 00:00:00

pages

445-58

issue

3

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(12)00740-X

journal_volume

48

pub_type

杂志文章

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