Three-dimensional chromatin ensemble reconstruction via stochastic embedding reveals a missing link from COVID-19 infection to anosmia.

Abstract

We propose a comprehensive method for reconstructing the whole-genome chromatin ensemble from the Hi-C data. The procedure starts from Markov state modeling (MSM), delineating the structural hierarchy of chromatin organization with partitioning and effective interactions archetypal for corresponding levels of hierarchy. The stochastic embedding procedure (SEP) provides the 3D ensemble reconstruction, using effective interactions obtained by the MSM as the input. As a result, we obtain the structural ensemble of a genome, allowing one to model the functional and the cell-type variability in the chromatin structure. Using SEP we investigate genomic mechanisms of a rapid onset and recovery from anosmia - a useful diagnostic indicator for early-stage COVID-19 infection. On the basis of published observations on how olfactory receptor (OR) gene expression is regulated via chromatin structure in mice, we hypothesized that the disruption of OR gene expression and, respectively, deficiency of OR function can be caused by chromatin reorganization taking place upon SARS-CoV-2 infection. We obtained chromatin ensemble reconstructions from COVID-19 patients and control samples using our original computational framework for whole-genome chromatin ensemble 3D reconstruction. We have also developed here an additional procedure for analyzing fine structural hierarchy in local, megabase scale, parts of chromosomes containing OR genes and corresponding regulatory elements. We observed structural modifications in COVID-19 patients on different levels of chromatin organization, from the alteration of whole genome structure and chromosomal intermingling to reorganization of contacts between chromatin loops at the level of topologically associating domains. While complementary data on known regulatory elements point to pathology-associated changes within the overall picture of chromatin alterations, further investigation using additional epigenetic factors mapped on 3D reconstructions with improved resolution will be required for better understanding of anosmia caused by SARS-CoV-2 infection.