The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation.
Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) has been previously proposed as a potential drug for use in substrate reduction therapy for mucopolysaccharidoses, a group of inherited metabolic diseases caused by mutations leading to inefficient degradation of glycosaminoglycans (GAGs) in lysosomes. It was demonstrated that this isoflavone can cross the blood-brain barrier, making it an especially desirable potential drug for the treatment of neurological symptoms present in most lysosomal storage diseases. So far, no comprehensive genomic analyses have been performed to elucidate the molecular mechanisms underlying the effect elicited by genistein. Therefore, the aim of this work was to identify the genistein-modulated gene network regulating GAG biosynthesis and degradation, taking into consideration the entire lysosomal metabolism. Our analyses identified over 60 genes with known roles in lysosomal biogenesis and/or function whose expression was enhanced by genistein. Moreover, 19 genes whose products are involved in both GAG synthesis and degradation pathways were found to be remarkably differentially regulated by genistein treatment. We found a regulatory network linking genistein-mediated control of transcription factor EB (TFEB) gene expression, TFEB nuclear translocation, and activation of TFEB-dependent lysosome biogenesis to lysosomal metabolism. Our data indicate that the molecular mechanism of genistein action involves not only impairment of GAG synthesis but more importantly lysosomal enhancement via TFEB. These findings contribute to explaining the beneficial effects of genistein in lysosomal storage diseases as well as envisage new therapeutic approaches to treat these devastating diseases.
From the Laboratory of Molecular Biology (affiliated with the University of Gdańsk), Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Wita Stwosza 59, 80-308 Gdańsk, Poland.
Marta
M
Moskot
the High Content Screening Facility, Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy.
Sandro
S
Montefusco
the Department of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland.
Joanna
J
Jakóbkiewicz-Banecka
the Department of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland.
Paweł
P
Mozolewski
the Department of Microbiology, University of Szczecin, Felczaka 3c, 71-412 Szczecin, Szczecin, Poland.
Alicja
A
Węgrzyn
the High Content Screening Facility, Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy.
Diego
D
Di Bernardo
the Department of Molecular Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland.
Grzegorz
G
Węgrzyn
the High Content Screening Facility, Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy, medina@tigem.it.
Diego L
DL
Medina
the High Content Screening Facility, Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy, the Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, the Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, and Medical Genetics, Department of Pediatrics, Federico II University, Via Pansini 5, 80131 Naples, Italy.
Andrea
A
Ballabio
From the Laboratory of Molecular Biology (affiliated with the University of Gdańsk), Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Wita Stwosza 59, 80-308 Gdańsk, Poland, m.gabig@biol.ug.edu.pl.
Magdalena
M
Gabig-Cimińska
D021581:Active Transport, Cell Nucleus; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D053263:Gene Regulatory Networks; D019833:Genistein / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D048789:Phytoestrogens / Q000494:pharmacology*; D014158:Transcription, Genetic
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006025:Glycosaminoglycans; D048789:Phytoestrogens; C064972:TFEB protein, human; D019833:Genistein
Flavonoid; Gene Expression; Genistein; Lysosomal Metabolism; Lysosomal Storage Disease; Microarray; Neurodegenerative Disease; Substrate Reduction Therapy; Transcriptomic Network Analysis; Transcriptomics