Genome-wide screens uncover KDM2B as a modifier of protein binding to heparan sulfate.
Nat Chem Biol
; 17(6): 684-692, 2021 06.
Article
de En
| MEDLINE
| ID: mdl-33846619
ABSTRACT
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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Protéines F-box
/
Étude d'association pangénomique
/
Jumonji Domain-Containing Histone Demethylases
/
Héparitine sulfate
Limites:
Humans
Langue:
En
Journal:
Nat Chem Biol
Sujet du journal:
BIOLOGIA
/
QUIMICA
Année:
2021
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique