Histone H2BK108Me2 Tunes Gluconeogenic Load in Type 2 Diabetes: A Molecular Dynamics Study

Abstract

Type 2 Diabetes (T2D) is a serious metabolic disorder characterised by hyperglycemia, hyperinsulinemia, and insulin resistance. An increased rate of hepatic gluconeogenesis acts as one of the major contributors of the high blood glucose levels in the diseased condition. Transcriptional regulation is a main factor that controls gene expression. In this study we have investigated how the transcriptional availability of the Cebpa gene can be modulated at the nucleosomal level through the post-translational modifications (PTMs) of histones using a series of coarse-grained multi-microsecond molecular dynamics (MD) simulations. Our work explores the structural modulations imposed by histone PTMs on the Cebpa +1 nucleosome in terms of histone-DNA interactions, nucleosome unwrapping, and nucleosome sliding, which can further contribute to the alteration in transcription of the gene. The MD simulations reveal that the histone mark H2BK108Me2--a downregulated histone PTM mark found in a diet-induced obese mouse liver--can steer the nucleosome sliding in a direction such that the transcription start site of Cebpa gene tends to close. This study predicts H2BK108Me2 to be a potential histone PTM mark which might be involved in tackling gluconeogenic load by closure of nucleosomal DNA ends of Cebpa +1 nucleosome via sliding and posing chromatin unavailability towards essential transcription factors of the gene. Author SummaryHistone PTMs regulate transcription of genes by altering nucleosome dynamics, yet, their precise mechanisms and effects remain unclear. Here, microsecond time-scale MD simulations with SIRAH forcefield reveals how T2D associated PTMs change DNA accessibility and reshape nucleosome conformation on the +1 nucleosome of a gluconeogenic regulator gene Cebpa. Our analysis uncovers changes in histone-DNA interactions, DNA trajectories, and nucleosome sliding to be the probable mechanisms of altered transcriptional output. This work attempts to bridge the gap between structural effects of nucleosomes and disease biology by providing a mechanistic link between metabolic disease epigenetics and chromatin biophysics. It demonstrates the role of PTMs in modulating the gene expression through collective nucleosome motions and offering insights into therapeutic targeting of histone PTMs.