Mesoscale modeling reveals formation of an epigenetically driven HOXC gene hub

Abstract

Gene expression is orchestrated at the structural level by nucleosome positioning, histone tail acetylation, and linker histone (LH) binding. Here, we integrate available data on nucleosome positioning, nucleosome-free regions (NFRs), acetylation islands, and LH binding sites to "fold" in silico the 55-kb HOXC gene cluster and investigate the role of each feature on the gene's folding. The gene cluster spontaneously forms a dynamic connection hub, characterized by hierarchical loops which accommodate multiple contacts simultaneously and decrease the average distance between promoters by ∼100 nm. Contact probability matrices exhibit "stripes" near promoter regions, a feature associated with transcriptional regulation. Interestingly, while LH proteins alone decrease long-range contacts and acetylation alone increases transient contacts, combined LH and acetylation produce long-range contacts. Thus, our work emphasizes how chromatin architecture is coordinated strongly by epigenetic factors and opens the way for nucleosome resolution models incorporating epigenetic modifications to understand and predict gene activity.chromatin modeling | chromatin folding | gene structure | chromatin loop domains | contact hub

Exploring Chromosomal Structural Heterogeneity Across Multiple Cell Lines

“…The heterogeneity has now been confirmed by direct imaging of individual chromosomal structures [14][15][16]. As a consequence of this conformational plasticity, statistical ensembles [25,26,29,30,[33][34][35][36][37][38] must be used in order to describe chromosomal structures in vivo.…”

Bridging chromatin structure and function over a range of experimental spatial and temporal scales by molecular modeling

“…All these features of directed folding were combined into our recent folding of the HOXC gene cluster to reveal a functionally important contact hub …”

“…Our group developed a mesoscale chromatin model where initially nucleosomes were flat cylinders with core electrostatics described by a set of Debye‐Hückel charges that reproduce the electric field around the atomistic nucleosome using the Poisson‐Boltzmann potential; linker DNA was treated using Stigter's worm‐like chain model . Further improvements in our chromatin model included the explicit description of histone tails as coarse‐grained beads, various LHs, epigenetic marks, implicit account of magnesium ions, and variable nucleosome positions . Validation against experimental data has shown that mesoscale models capture the essential physical properties of chromatin fibers, and thus contribute to our understanding of the different levels of DNA organization inside the cell and their relevance to regulation of gene expression .…”

Computing 3D chromatin configurations from contact probability maps by Inverse Brownian Dynamics

“…Several attempts have been made to understand the 3D organization of the genome using a variety of techniques developed previously to understand the statics and dynamics of polymers (15)(16)(17)(18)(19)(20)(21)(22). Early models revealed both the fractal nature of individual chromosome folding and the larger scale packing of all the chromosomes into TADs of various sizes (23,24).…”