NAD+-SIRT1 control of H3K4 trimethylation through circadian deacetylation of MLL1

Lorena Aguilar-Arnal, Sayako Katada, Ricardo Orozco-Solis, Paolo Sassone-Corsi

Research output: Contribution to journalArticlepeer-review

57 Citations (Scopus)

Abstract

The circadian clock controls the transcription of hundreds of genes through specific chromatin-remodeling events. The histone methyltransferase mixed-lineage leukemia 1 (MLL1) coordinates recruitment of CLOCK-BMAL1 activator complexes to chromatin, an event associated with cyclic trimethylation of histone H3 Lys4 (H3K4) at circadian promoters. Remarkably, in mouse liver circadian H3K4 trimethylation is modulated by SIRT1, an NAD+-dependent deacetylase involved in clock control. We show that mammalian MLL1 is acetylated at two conserved residues, K1130 and K1133. Notably, MLL1 acetylation is cyclic, controlled by the clock and by SIRT1, and it affects the methyltransferase activity of MLL1. Moreover, H3K4 methylation at clock-controlled-gene promoters is influenced by pharmacological or genetic inactivation of SIRT1. Finally, levels of MLL1 acetylation and H3K4 trimethylation at circadian gene promoters depend on NAD+ circadian levels. These findings reveal a previously unappreciated regulatory pathway between energy metabolism and histone methylation.

Original languageEnglish
Pages (from-to)312-318
Number of pages7
JournalNature Structural and Molecular Biology
Volume22
Issue number4
DOIs
Publication statusPublished - Apr 7 2015

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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