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Genome-wide screens uncover KDM2B as a modifier of protein binding to heparan sulfate.
Weiss, Ryan J; Spahn, Philipp N; Chiang, Austin W T; Liu, Qing; Li, Jing; Hamill, Kristina M; Rother, Sandra; Clausen, Thomas M; Hoeksema, Marten A; Timm, Bryce M; Godula, Kamil; Glass, Christopher K; Tor, Yitzhak; Gordts, Philip L S M; Lewis, Nathan E; Esko, Jeffrey D.
Afiliação
  • Weiss RJ; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Spahn PN; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
  • Chiang AWT; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
  • Liu Q; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Li J; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Hamill KM; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • Rother S; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Clausen TM; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Hoeksema MA; Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital, Copenhagen, Denmark.
  • Timm BM; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Godula K; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • Glass CK; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
  • Tor Y; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA.
  • Gordts PLSM; Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Lewis NE; Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • Esko JD; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA.
Nat Chem Biol ; 17(6): 684-692, 2021 06.
Article em En | MEDLINE | ID: mdl-33846619
Heparan sulfate (HS) proteoglycans bind extracellular proteins that participate in cell signaling, attachment and endocytosis. These interactions depend on the arrangement of sulfated sugars in the HS chains generated by well-characterized biosynthetic enzymes; however, the regulation of these enzymes is largely unknown. We conducted genome-wide CRISPR-Cas9 screens with a small-molecule ligand that binds to HS. Screening of A375 melanoma cells uncovered additional genes and pathways impacting HS formation. The top hit was the epigenetic factor KDM2B, a histone demethylase. KDM2B inactivation suppressed multiple HS sulfotransferases and upregulated the sulfatase SULF1. These changes differentially affected the interaction of HS-binding proteins. KDM2B-deficient cells displayed decreased growth rates, which was rescued by SULF1 inactivation. In addition, KDM2B deficiency altered the expression of many extracellular matrix genes. Thus, KDM2B controls proliferation of A375 cells through the regulation of HS structure and serves as a master regulator of the extracellular matrix.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas F-Box / Estudo de Associação Genômica Ampla / Histona Desmetilases com o Domínio Jumonji / Heparitina Sulfato Limite: Humans Idioma: En Revista: Nat Chem Biol Assunto da revista: BIOLOGIA / QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas F-Box / Estudo de Associação Genômica Ampla / Histona Desmetilases com o Domínio Jumonji / Heparitina Sulfato Limite: Humans Idioma: En Revista: Nat Chem Biol Assunto da revista: BIOLOGIA / QUIMICA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos