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Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process

Author

Listed:
  • Chao Wang

    (Scripps Research)

  • Samantha M. Scott

    (Scripps Research)

  • Kanagaraj Subramanian

    (Scripps Research)

  • Salvatore Loguercio

    (Scripps Research)

  • Pei Zhao

    (Scripps Research)

  • Darren M. Hutt

    (Scripps Research)

  • Nicole Y. Farhat

    (National Institutes of Health)

  • Forbes D. Porter

    (National Institutes of Health)

  • William E. Balch

    (Scripps Research)

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 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.

Suggested Citation

  • Chao Wang & Samantha M. Scott & Kanagaraj Subramanian & Salvatore Loguercio & Pei Zhao & Darren M. Hutt & Nicole Y. Farhat & Forbes D. Porter & William E. Balch, 2019. "Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12969-x
    DOI: 10.1038/s41467-019-12969-x
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    Cited by:

    1. Pei Zhao & Chao Wang & Shuhong Sun & Xi Wang & William E. Balch, 2024. "Tracing genetic diversity captures the molecular basis of misfolding disease," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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