The malignant brain tumor (MBT) domain protein SFMBT1 is an integral histone reader subunit of the LSD1 demethylase complex for chromatin association and epithelial-to-mesenchymal transition.
Chromatin readers decipher the functional readouts of histone modifications by recruiting specific effector complexes for subsequent epigenetic reprogramming. The LSD1 (also known as KDM1A) histone demethylase complex modifies chromatin and represses transcription in part by catalyzing demethylation of dimethylated histone H3 lysine 4 (H3K4me2), a mark for active transcription. However, none of its currently known subunits recognizes methylated histones. The Snai1 family transcription factors are central drivers of epithelial-to-mesenchymal transition (EMT) by which epithelial cells acquire enhanced invasiveness. Snai1-mediated transcriptional repression of epithelial genes depends on its recruitment of the LSD1 complex and ensuing demethylation of H3K4me2 at its target genes. Through biochemical purification, we identified the MBT domain-containing protein SFMBT1 as a novel component of the LSD1 complex associated with Snai1. Unlike other mammalian MBT domain proteins characterized to date that selectively recognize mono- and dimethylated lysines, SFMBT1 binds di- and trimethyl H3K4, both of which are enriched at active promoters. We show that SFMBT1 is essential for Snai1-dependent recruitment of LSD1 to chromatin, demethylation of H3K4me2, transcriptional repression of epithelial markers, and induction of EMT by TGFβ. Carcinogenic metal nickel is a widespread environmental and occupational pollutant. Nickel alters gene expression and induces EMT. We demonstrate the nickel-initiated effects are dependent on LSD1-SFMBT1-mediated chromatin modification. Furthermore, in human cancer, expression of SFMBT1 is associated with mesenchymal markers and unfavorable prognosis. These results highlight a critical role of SFMBT1 in epigenetic regulation, EMT, and cancer.
Department of Biochemistry and Molecular Biology; Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida 32610.
Ming
M
Tang
Department of Molecular Genetics and Microbiology; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060 China.
Huangxuan
H
Shen
Department of Biochemistry and Molecular Biology.
Yue
Y
Jin
Department of Biochemistry and Molecular Biology; Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida 32610.
Tong
T
Lin
Department of Biochemistry and Molecular Biology.
Qingsong
Q
Cai
Department of Biochemistry and Molecular Biology.
Melissa A
MA
Pinard
Department of Biochemistry and Molecular Biology.
Shyamasri
S
Biswas
Agnes Scott College, Decatur, Georgia 30030.
Quyen
Q
Tran
Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida 32610; Department of Molecular Genetics and Microbiology.
Guangyao
G
Li
Department of Biochemistry and Molecular Biology.
Anitha K
AK
Shenoy
Department of Biochemistry and Molecular Biology.
Emily
E
Tongdee
Department of Molecular Genetics and Microbiology.
Shuibin
S
Lin
Department of Molecular Genetics and Microbiology.
Yumei
Y
Gu
Department of Pharmacology and Therapeutics, Health Cancer Center, University of Florida College of Medicine, Gainesville, Florida 32610.
Brian K
BK
Law
Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida 32610; Department of Molecular Genetics and Microbiology.
Lei
L
Zhou
Department of Biochemistry and Molecular Biology.
Robert
R
Mckenna
Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida 32610; Department of Molecular Genetics and Microbiology. Electronic address: lzwu@ufl.edu.
Lizi
L
Wu
Department of Biochemistry and Molecular Biology; Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, Florida 32610. Electronic address: jrlu@ufl.edu.
Jianrong
J
Lu
D002273:Carcinogens / Q000494:pharmacology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009532:Nickel / Q000009:adverse effects / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014131:Trace Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D002273:Carcinogens; D002843:Chromatin; D006657:Histones; D009363:Neoplasm Proteins; D012097:Repressor Proteins; C523369:SFMBT1 protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014131:Trace Elements; D014157:Transcription Factors; D009532:Nickel; D056466:Histone Demethylases; C495195:KDM1A protein, human
Cell Invasion; Chromatin Histone Modification; Epigenetics; Epithelial-to-mesenchymal Transition; Nickel; Transcription Repressor