Genome-wide screens uncover KDM2B as a modifier of protein binding to heparan sulfate
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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.
In: Nature Chemical Biology, Vol. 17, 2021, p. 684–692.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Genome-wide screens uncover KDM2B as a modifier of protein binding to heparan sulfate
AU - Weiss, Ryan J.
AU - Spahn, Philipp N.
AU - Chiang, Austin W.T.
AU - Liu, Qing
AU - Li, Jing
AU - Hamill, Kristina M.
AU - Rother, Sandra
AU - Clausen, Thomas M.
AU - Hoeksema, Marten A.
AU - Timm, Bryce M.
AU - Godula, Kamil
AU - Glass, Christopher K.
AU - Tor, Yitzhak
AU - Gordts, Philip L.S.M.
AU - Lewis, Nathan E.
AU - Esko, Jeffrey D.
PY - 2021
Y1 - 2021
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
U2 - 10.1038/s41589-021-00776-9
DO - 10.1038/s41589-021-00776-9
M3 - Journal article
C2 - 33846619
AN - SCOPUS:85104253089
VL - 17
SP - 684
EP - 692
JO - Nature Chemical Biology
JF - Nature Chemical Biology
SN - 1552-4450
ER -
ID: 260548074