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

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 elucidated 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 simulations. The transcriptional status of a gene is influenced by a plethora of factors, but our work reveals that indeed histone PTMs are capable of modulating transcriptional output of genes at a structural level, independent of other regulatory factors. We have identified H2BK108Me2--a downregulated histone PTM mark found in a diet-induced obese mouse liver--to be essentially contributing in tackling gluconeogenic load by suppressing transcription of the Cebpa gene. We found that H2BK108Me2 induces the closure of the nucleosomal DNA ends through sliding and posing chromatin unavailability towards essential transcription factors of the gene. Statement of SignificanceHistone 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 on disease biology, by providing a mechanistic link between metabolic disease epigenetics and chromatin biophysics, demonstrating the role of PTMs in modulating the gene expression through collective nucleosome motions and offering insights into therapeutic targeting of histone PTMs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/699059v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1ab68beorg.highwire.dtl.DTLVardef@69a43dorg.highwire.dtl.DTLVardef@19dc6f5org.highwire.dtl.DTLVardef@1712ed7_HPS_FORMAT_FIGEXP M_FIG C_FIG