Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement.

MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.

Epigenetic modulators provide a path to understanding disease and therapeutic opportunity.

The discovery of epigenetic modulators (writers, erasers, readers, and remodelers) has shed light on previously underappreciated biological mechanisms that promote diseases. With these insights, novel biomarkers and innovative combination therapies can be used to address challenging and difficult to treat disease states. This review highlights key mechanisms that epigenetic writers, erasers, readers, and remodelers control, as well as their connection with disease states and recent advances in associated epigenetic therapies.

Orcokinin neuropeptides regulate sleep in Caenorhabditis elegans.

Orcokinin neuropeptides are conserved among ecdysozoans, but their functions are incompletely understood. Here, we report a role for orcokinin neuropeptides in the regulation of sleep in the nematode Caenorhabditis elegans. The C. elegans orcokinin peptides, which are encoded by the nlp-14 and nlp-15 genes, are necessary and sufficient for quiescent behaviors during developmentally timed sleep (DTS) as well as during stress-induced sleep (SIS). The five orcokinin neuropeptides encoded by nlp-14 have distinct but overlapping functions in the regulation of movement and defecation quiescence during SIS. We suggest that orcokinins may regulate behavioral components of sleep-like states in nematodes and other ecdysozoans.

The neuropeptide receptor npr-38 regulates avoidance and stress-induced sleep in Caenorhabditis elegans.

Although essential and conserved, sleep is not without its challenges that must be overcome; most notably, it renders animals vulnerable to threats in the environment. Infection and injury increase sleep demand, which dampens sensory responsiveness to stimuli, including those responsible for the initial insult. Stress-induced sleep in Caenorhabditis elegans occurs in response to cellular damage following noxious exposures the animals attempted to avoid. Here, we describe a G-protein-coupled receptor (GPCR) encoded by npr-38, which is required for stress-related responses including avoidance, sleep, and arousal. Overexpression of npr-38 shortens the avoidance phase and causes animals to initiate movement quiescence and arouse early. npr-38 functions in the ADL sensory neurons, which express neuropeptides encoded by nlp-50, also required for movement quiescence. npr-38 regulates arousal by acting on the DVA and RIS interneurons. Our work demonstrates that this single GPCR regulates multiple aspects of the stress response by functioning in sensory and sleep interneurons.