title: Genome-wide RNAi ionomics screen reveals new genes and regulation of human trace element metabolism.
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.
authors: 1] Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, USA.
authors: Mikalai
authors: M
authors: Malinouski
authors: Department of Physiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors: Nesrin M
authors: NM
authors: Hasan
authors: 1] Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA [2] Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors: Yan
authors: Y
authors: Zhang
authors: Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588, USA.
authors: Javier
authors: J
authors: Seravalli
authors: 1] Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China [2] Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors: Jie
authors: J
authors: Lin
authors: Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Andrei
authors: A
authors: Avanesov
authors: Department of Physiology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors: Svetlana
authors: S
authors: Lutsenko
authors: Genetics Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Vadim N
authors: VN
authors: Gladyshev
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D000073840:Copper-Transporting ATPases; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D013058:Mass Spectrometry; D034741:RNA, Small Interfering; D012643:Selenium / Q000378:metabolism; D014131:Trace Elements / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D034741:RNA, Small Interfering; D014131:Trace Elements; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases; D012643:Selenium