Department of Molecular Medicine, Scripps Research, La Jolla, CA, 92037, USA.
Section on Molecular Dysmorphology, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20814, USA.
Nat Commun. 2019 Nov 7;10(1):5052. doi: 10.1038/s41467-019-12969-x.
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 the spatial covariance (SCV) relationships that link genetic diversity to fitness of the individual in response to histone deacetylases inhibitors (HDACi). Niemann-Pick C1 (NPC1) is a Mendelian disorder caused by >300 variants in the NPC1 gene that disrupt cholesterol homeostasis leading to the rapid onset and progression of neurodegenerative disease. We determine the sequence-to-function-to-structure relationships of the NPC1 polypeptide fold required for membrane trafficking and generation of a tunnel that mediates cholesterol flux in late endosomal/lysosomal (LE/Ly) compartments. HDACi treatment reveals unanticipated epigenomic plasticity in SCV relationships that restore NPC1 functionality. GPR-ML based matrices capture the epigenetic processes impacting information flow through central dogma, providing a framework for quantifying the effect of the environment on the healthspan of the individual.
为了理解表观遗传学对人类错误折叠疾病的影响，我们通过变分空间分析（VSP）应用了基于高斯过程回归（GPR）的机器学习（ML）（GPR-ML）。VSP 生成基于人群的矩阵，描述了连接遗传多样性与个体对组蛋白去乙酰化酶抑制剂（HDACi）适应能力的空间协方差（SCV）关系。尼曼-匹克 C1 型（NPC1）是一种孟德尔疾病，由 NPC1 基因中的 >300 种变异引起，这些变异破坏了胆固醇的动态平衡，导致神经退行性疾病的快速发作和进展。我们确定 NPC1 多肽折叠所需的序列-功能-结构关系，该折叠对于膜运输和形成隧道至关重要，该隧道介导晚期内体/溶酶体（LE/Ly）隔室中的胆固醇通量。HDACi 治疗揭示了 SCV 关系中出乎意料的表观遗传可塑性，恢复了 NPC1 的功能。基于 GPR-ML 的矩阵捕捉了影响中心法则信息流的表观遗传过程，为量化环境对个体健康寿命的影响提供了框架。
