Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process

• DOI: 10.1038/s41467-019-12969-x
• Publication Date: 2019-11-07T11:05:58Z
• Authors: Chao Wang; Samantha M. Scott; Kanagaraj Subrama...; Salvatore Loguercio; Pei Zhao; Darren M. Hutt; Nicole Y. Farhat; Forbes D. Porter; William E. Balch
• Keywords: NPC1; Epigenomics

Abstract To understand the impact of epigenetics on human misfolding disease, we apply Gaussian-process regression (GPR) based machine learning (ML) (GPR-ML) through variation spatial profiling (VSP). VSP generates population-based matrices describing covariance (SCV) relationships that link genetic diversity to fitness individual in response histone deacetylases inhibitors (HDACi). Niemann-Pick C1 (NPC1) is a Mendelian disorder caused by >300 variants NPC1 gene disrupt cholesterol homeostasis leading rapid onset and progression neurodegenerative disease. We determine sequence-to-function-to-structure polypeptide fold required for membrane trafficking generation tunnel mediates flux late endosomal/lysosomal (LE/Ly) compartments. HDACi treatment reveals unanticipated epigenomic plasticity SCV restore functionality. GPR-ML capture epigenetic processes impacting information flow central dogma, providing framework quantifying effect environment healthspan individual.