NXPE1 alters the sialoglycome by acetylating sialic acids in the human colon

Bum Seok Lee, Ashley Cook, Surojit Sur, Laura Dobbyn, Maria Popoli, Sana Khalili, Shibin Zhou, Chetan Bettegowda, Nickolas Papadopoulos, Kathy Gabrielson, Phillip Buckhaults, Bert Vogelstein, Kenneth W. Kinzler () and Nicolas Wyhs ()
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Bum Seok Lee: Johns Hopkins University School of Medicine
Ashley Cook: Johns Hopkins University School of Medicine
Surojit Sur: Johns Hopkins University School of Medicine
Laura Dobbyn: Johns Hopkins Medical Institutions
Maria Popoli: Johns Hopkins University School of Medicine
Sana Khalili: University of South Carolina
Shibin Zhou: Johns Hopkins University School of Medicine
Chetan Bettegowda: Johns Hopkins University School of Medicine
Nickolas Papadopoulos: Johns Hopkins University School of Medicine
Kathy Gabrielson: Johns Hopkins University School of Medicine
Phillip Buckhaults: University of South Carolina
Bert Vogelstein: Johns Hopkins University School of Medicine
Kenneth W. Kinzler: Johns Hopkins University School of Medicine
Nicolas Wyhs: Johns Hopkins University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Mild periodic acid Schiff staining (mPAS) of human colonic tissue has been used to answer a variety of fundamental questions in germline and somatic genetics. mPAS stains sialic acids except when these glycans are modified by O-acetylation, but a full accounting of the genes contributing to sialoglycan acetylation is incomplete. Using haplotypes derived from whole genome sequencing, we identify a region on chromosome 11 that is associated with inherited differences in mPAS staining. Of the genes in this region, only haplotypes containing NXPE1 correlate perfectly with mPAS staining in the original cohort used for whole genome sequencing, as well as in a validation cohort. Transcriptomic analysis indicates that linked haplotypes are associated with altered expression of NXPE1 suggesting a possible genetic mechanism. Genetic manipulation of a common single nucleotide polymorphism observed in the haplotype region and located in NXPE1’s promoter alters expression and causes changes to modified sialic acid levels supporting this mechanism. Finally, high-performance liquid chromatography (HPLC) confirms that enzymatically active NXPE1 is capable of transferring an acetyl group from acetyl coenzyme A to sialic acid in vitro. These findings suggest that NXPE1 is the long-sought gene responsible for differences in colon mPAS staining and may be the prototype of a new family of sialic acid O-acetylation-modifying genes.

Date: 2025
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DOI: 10.1038/s41467-025-59671-9

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