DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin.

The proto-oncogene c-MYC is a key representative of the MYC transcription factor network regulating growth and metabolism. MML-1 (Myc- and Mondo-like) is its homolog in . The functional and molecular cooperation between c-MYC and H3 lysine 79 methyltransferase DOT1L was demonstrated in several human cancer types, and we have earlier discovered the connection between MML-1 and DOT-1.

The proline-rich domain of MML-1 is biologically important but not required for localization to target promoters.

The only representative of the MYC superfamily transcription factors in , MML-1 (Myc and Mondo-like 1), was shown to promote extended lifespan in a variety of models and to regulate some aspects of development. This previous research did not involve molecular characterization of MML-1. Here we use available mutant alleles and other reagents to demonstrate that MML-1 is modified by -GlcNAc, binds to promoters of some genes directly regulated by the DOT-1.

Deficient in DOT-1.1 Exhibit Increases in H3K9me2 at Enhancer and Certain RNAi-Regulated Regions.

The methylation of histone H3 at lysine 79 is a feature of open chromatin. It is deposited by the conserved histone methyltransferase DOT1. Recently, DOT1 localization and H3K79 methylation (H3K79me) have been correlated with enhancers in and mammalian cells.

DOT1L complex suppresses transcription from enhancer elements and ectopic RNAi in .

Methylation of histone H3 on lysine 79 (H3K79) by DOT1L is associated with actively transcribed genes. Earlier, we described that DOT-1.1, the homolog of mammalian DOT1L, cooperates with the chromatin-binding protein ZFP-1 (AF10 homolog) to negatively modulate transcription of highly and widely expressed target genes.

Interplay between small RNA pathways shapes chromatin landscapes in C. elegans.

The nematode Caenorhabditis elegans contains several types of endogenous small interfering RNAs (endo-siRNAs) produced by RNA-dependent RNA polymerase (RdRP) complexes. Both 'silencing' siRNAs bound by Worm-specific Argonautes (WAGO) and 'activating' siRNAs bound by the CSR-1 Argonaute require the DRH-3 helicase, an RdRP component. Here, we show that, in the drh-3(ne4253) mutant deficient in RdRP-produced secondary endo-siRNAs, the silencing histone mark H3K9me3 is largely depleted, whereas in the csr-1 partially rescued null mutant strain (WM193), this mark is ectopically deposited on CSR-1 target genes.