A SirT'N repression for Notch

Abstract

Mulligan et al. (2011) show here that the NAD(+)-dependent SIRT1 (H4K16; H1K26) deacetylase acts in concert with the LSD1 (H3K4) demethylase to repress Notch-induced transcription, thus coupling two distinct histone modifications at a key epigenetic switch for Notch target genes.

Figure 1. Model of Notch-Regulated Transcription at Target Gene Core Promoters

(A) Corepressors targeted to CSL-bound promoters in the absence of Notch signaling (left) includes SirT1, LSD1, CtBP, Co-REST, and EHMT. Other factors that contribute to Notch repression include the Rpd3:LID:Sin3A and SMRT:HDAC1 complexes, Cir-1, and SHARP. Upon signaling (right), the NICD interacts directly with CSL, Mastermind (MAML), and SKIP. Notch transactivation also requires H2B ubiquitylation and the PAF1 complex. (B) An epigenetic switch is created downstream of H2Bub at MLL1-dependent core promoters. The H3K4me3 and H4K16ac modification are “written” jointly by the physically interacting MLL1 and hMOF complexes, “read” through binding of the BPTF NURF nucleosome remodeling factor complex subunit, and “erased” in tandem, through the concerted actions of the SirT1-LSD1 corepressor complex. Other factors that bind these modified histones are mentioned in the text.