@article{3a0d4a867ec84773a35aaa4fa098040b,
title = "Genome-wide screens uncover KDM2B as a modifier of protein binding to heparan sulfate",
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. [Figure not available: see fulltext.]",
author = "Weiss, {Ryan J.} and Spahn, {Philipp N.} and Chiang, {Austin W. T.} and Qing Liu and Jing Li and Hamill, {Kristina M.} and Sandra Rother and Clausen, {Thomas M.} and Hoeksema, {Marten A.} and Timm, {Bryce M.} and Kamil Godula and Glass, {Christopher K.} and Yitzhak Tor and Gordts, {Philip L. S. M.} and Lewis, {Nathan E.} and Esko, {Jeffrey D.}",
note = "Funding Information: We thank C. van der Kooi, University of Kentucky, for providing the b1b2 domain of NRP1, and D. Xu, University of Buffalo, for providing the biotinylated S100A12 protein. We also thank the GlycoAnalytics Core Facility at University of California, San Diego for help with analytical experiments. We thank C. Kuo for processing of RNA sequencing data. RNA sequencing and CRISPR amplicon sequencing were conducted at the IGM Genomics Center, University of California, San Diego, La Jolla, CA (MCC grant no. P30CA023100). This work was supported by grant nos. R21 CA199292 (to J.D.E. and N.E.L.), GM33063 (to J.D.E.), GM119850 (to N.E.L.), NSF CHE 200424 (to K.G.) and T32 GM008326 (fellowship support for B.M.T.); and DFG research fellowship no. 420160411 from the German Research Foundation (to S.R.) and no. K12HL141956 (fellowship support for R.J.W.). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = jun,
day = "1",
doi = "https://doi.org/10.1038/s41589-021-00776-9",
language = "English",
volume = "17",
pages = "684--692",
journal = "Nature chemical biology",
issn = "1552-4450",
publisher = "Nature Publishing Group",
number = "6",
}