DOT1L activity in leukemia cells requires interaction with ubiquitylated H2B that promotes productive nucleosome binding.

DOT1L methylates histone H3 lysine 79 during transcriptional elongation and is stimulated by ubiquitylation of histone H2B lysine 120 (H2BK120ub) in a classical trans-histone crosstalk pathway. Aberrant genomic localization of DOT1L is implicated in mixed lineage leukemia (MLL)-rearranged leukemias, an aggressive subset of leukemias that lacks effective targeted treatments. Despite recent atomic structures of DOT1L in complex with H2BK120ub nucleosomes, fundamental questions remain as to how DOT1L-ubiquitin and DOT1L-nucleosome acidic patch interactions observed in these structures contribute to nucleosome binding and methylation by DOT1L.

Prior Binge Ethanol Exposure Potentiates the Microglial Response in a Model of Alcohol-Induced Neurodegeneration.

Excessive alcohol consumption results in neurodegeneration which some hypothesize is caused by neuroinflammation. One characteristic of neuroinflammation is microglial activation, but it is now well accepted that microglial activation may be pro- or anti-inflammatory. Recent work indicates that the Majchrowicz model of alcohol-induced neurodegeneration results in anti-inflammatory microglia, while intermittent exposure models with lower doses and blood alcohol levels produce microglia with a pro-inflammatory phenotype.

Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects.

Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may be one route by which alcohol produces hippocampal neuropathology.

Neuroimmune regulation of alcohol consumption: behavioral validation of genes obtained from genomic studies.

Analysis of mouse brain gene expression, using strains that differ in alcohol consumption, provided a number of novel candidate genes that potentially regulate alcohol consumption. We selected six genes [beta-2-microglobulin (B2m), cathepsin S (Ctss), cathepsin F (Ctsf), interleukin 1 receptor antagonist (Il1rn), CD14 molecule (Cd14) and interleukin 6 (Il6)] for behavioral validation using null mutant mice. These genes are known to be important for immune responses but were not specifically linked to alcohol consumption by previous research.

Activation of inflammatory signaling by lipopolysaccharide produces a prolonged increase of voluntary alcohol intake in mice.

Previous studies showed that mice with genetic predisposition for high alcohol consumption as well as human alcoholics show changes in brain expression of genes related to immune signaling. In addition, mutant mice lacking genes related to immune function show decreased alcohol consumption (Blednov et al., 2011), suggesting that immune signaling promotes alcohol consumption.