Histone methyltransferase MLL3 contributes to genome-scale circadian transcription

Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1554-9. doi: 10.1073/pnas.1214168110. Epub 2013 Jan 7.


Daily cyclical expression of thousands of genes in tissues such as the liver is orchestrated by the molecular circadian clock, the disruption of which is implicated in metabolic disorders and cancer. Although we understand much about the circadian transcription factors that can switch gene expression on and off, it is still unclear how global changes in rhythmic transcription are controlled at the genomic level. Here, we demonstrate circadian modification of an activating histone mark at a significant proportion of gene loci that undergo daily transcription, implicating widespread epigenetic modification as a key node regulated by the clockwork. Furthermore, we identify the histone-remodelling enzyme mixed lineage leukemia (MLL)3 as a clock-controlled factor that is able to directly and indirectly modulate over a hundred epigenetically targeted circadian "output" genes in the liver. Importantly, catalytic inactivation of the histone methyltransferase activity of MLL3 also severely compromises the oscillation of "core" clock gene promoters, including Bmal1, mCry1, mPer2, and Rev-erbα, suggesting that rhythmic histone methylation is vital for robust transcriptional oscillator function. This highlights a pathway by which the clockwork exerts genome-wide control over transcription, which is critical for sustaining temporal programming of tissue physiology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ARNTL Transcription Factors / genetics
  • Animals
  • Cell Line
  • Circadian Rhythm / genetics*
  • Circadian Rhythm / physiology*
  • Cryptochromes / deficiency
  • Cryptochromes / genetics
  • Epigenomics
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics
  • Period Circadian Proteins / genetics
  • Promoter Regions, Genetic
  • Systems Biology
  • Transcription, Genetic


  • ARNTL Transcription Factors
  • Arntl protein, mouse
  • Cry1 protein, mouse
  • Cry2 protein, mouse
  • Cryptochromes
  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Per2 protein, mouse
  • Period Circadian Proteins
  • Histone-Lysine N-Methyltransferase
  • MLL3 protein, mouse

Associated data

  • GEO/GSE23550
  • GEO/GSE37396