Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism

Nat Commun. 2014;5:3301. doi: 10.1038/ncomms4301.

Abstract

Trace elements are essential for human metabolism and dysregulation of their homoeostasis is associated with numerous disorders. Here we characterize mechanisms that regulate trace elements in human cells by designing and performing a genome-wide high-throughput siRNA/ionomics screen, and examining top hits in cellular and biochemical assays. The screen reveals high stability of the ionomes, especially the zinc ionome, and yields known regulators and novel candidates. We further uncover fundamental differences in the regulation of different trace elements. Specifically, selenium levels are controlled through the selenocysteine machinery and expression of abundant selenoproteins; copper balance is affected by lipid metabolism and requires machinery involved in protein trafficking and post-translational modifications; and the iron levels are influenced by iron import and expression of the iron/haeme-containing enzymes. Our approach can be applied to a variety of disease models and/or nutritional conditions, and the generated data set opens new directions for studies of human trace element metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Cation Transport Proteins / metabolism
  • Cell Line, Tumor
  • Copper-Transporting ATPases
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Mass Spectrometry
  • RNA, Small Interfering
  • Selenium / metabolism
  • Trace Elements / metabolism*

Substances

  • Cation Transport Proteins
  • RNA, Small Interfering
  • Trace Elements
  • Adenosine Triphosphatases
  • ATP7A protein, human
  • Copper-Transporting ATPases
  • Selenium