A SIRT1-LSD1 Corepressor Complex Regulates Notch Target Gene Expression and Development

Abstract

Summary Epigenetic regulation of gene expression by histone-modifying co-repressor complexes is central to normal animal development. The NAD+-dependent deacetylase and gene repressor SIRT1 removes histone H4K16 acetylation marks and facilitates heterochromatin formation. However, the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci and whether it acts in concert with other chromatin-modifying activities to control developmental gene expression programs remain unclear. We describe here a SIRT1 co-repressor complex containing the histone H3K4 demethylase LSD1/KDM1A and several other LSD1-associated proteins. SIRT1 and LSD1 interact directly and play conserved and concerted roles in H4K16 deacetylation and H3K4 demethylation to repress genes regulated by the Notch signaling pathway. Mutations in Drosophila SIRT1 and LSD1 orthologs result in similar developmental phenotypes and genetically interact with the Notch pathway in Drosophila. These findings offer new insights into conserved mechanisms of epigenetic gene repression and regulation of development by SIRT1 in metazoans.

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…Indeed, KDM1A depletion in mice impairs neuronal migration [35]. Consistent with these data, KDM1A interacts during Drosophila development with the histone deacetylase SIRT1 to negatively regulate Notch target gene expression by modifying histone modifications [36].…”

Acetylation controls Notch3 stability and function in T-cell leukemia

“…Moreover, in a more recent paper, besides the Notch1 degradation by Sirt1-sustained deacetylation, Notch1 target gene expression was driven by the repressory action of Sirt1/LSD1 complex deacetylating and demethylating chromatin. (Mulligan et al, 2011).…”

Dynamic binding of RBPJ is determined by Notch signaling status

“…It has been shown that removal of RBPJ/Su(H) in the absence of NICD results in the transient activation (derepression) of some target genes (Morel and Schweisguth 2000;Koelzer and Klein 2003;Mulligan et al 2011;Yatim et al 2012). Our observation that RBPJ occupancy is strongly reduced at the inducible sites under Notch-off conditions prompted us to measure directly the repressive function of endogenous RBPJ in primary myogenic cells.…”