Chebolu, S. | Search bioRxiv

bioRxiv2026

DOT1L-AF10-mediated H3K79me3 promotes NF-kB p65-dependent inflammatory activation in endothelial cells

DOT1L-catalyzed H3K79 methylation is a hallmark of actively transcribed genes and has been extensively studied in developmental and disease contexts. While DOT1L inhibition has emerged as a promising therapeutic strategy in cancer, its role in pro-atherogenic endothelial inflammation remains unclear. To investigate this, we utilized an in vivo partial carotid artery ligation model and observed increased DOT1L expression and H3K79me3 level. Consistently, in vitro studies employing a 3D-printed human coronary artery model and TNF- stimulation corroborated these results, showing elevated DOT1L expression and H3K79me3 deposition, while levels of H3K79me and me2 remained unchanged. Further analyses identified key DOT1L-containing complex (DotCom) components, AF10 and AF9 (upregulated) and AF17 (downregulated), as contributors to the enhanced H3K79me3 landscape. CUT&RUN sequencing showed prominent H3K79me3 enrichment at the RELA (NF-{kappa}B p65) promoter, corresponding with increased NF-{kappa}B p65 expression and activation. Notably, inhibition/knockdown of the methyltransferase DOT1L or overexpression of the demethylase FBXL10 significantly reduced H3K79me3 levels, thereby suppressing NF-{kappa}B p65 expression and attenuating endothelial inflammation, independent of canonical NF-{kappa}B p65 activation. These findings establish DOT1L-mediated H3K79me3 as a crucial epigenetic regulator of endothelial inflammation, highlighting a potential therapeutic avenue for mitigating NF-{kappa}B p65-driven pro-atherogenic endothelial dysfunction.

cell biology↗

bioRxiv2022

Vigilance, arousal, and acetylcholine: Optimal control of attention in a simple detection task

Paying attention to particular aspects of the world or being more vigilant in general can be interpreted as forms of internal action. Such arousal-related choices come with the benefit of increasing the quality and situational appropriateness of information acquisition and processing, but incur potentially expensive energetic and opportunity costs. One implementational route for these choices is widespread ascending neuromodulation, including by acetylcholine (ACh). The key computational question that elective attention poses for sensory processing is when it is worthwhile paying these costs, and this includes consideration of whether sufficient information has yet been collected to justify the higher signal-to-noise ratio afforded by greater attention and, particularly if a change in attentional state is more expensive than its maintenance, when states of heightened attention ought to persist. We offer a partially observable Markov decision-process treatment of optional attention in a detection task, and use it to provide a qualitative model of the results of studies using modern techniques to measure and manipulate ACh in rodents performing a similar task.

neuroscience↗