Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Elucidation of the low-expressing erythroid CR1 phenotype by bioinformatic mining of the GATA1-driven blood-group regulome

Wu, Ping Chun LU orcid ; Lee, Yan Quan LU ; Möller, Mattias LU orcid ; Storry, Jill R LU and Olsson, Martin L LU orcid (2023) In Nature Communications 14(1).
Abstract

Genetic determinants underlying most human blood groups are now clarified but variation in expression levels remains largely unexplored. By developing a bioinformatics pipeline analyzing GATA1/Chromatin immunoprecipitation followed by sequencing (ChIP-seq) datasets, we identify 193 potential regulatory sites in 33 blood-group genes. As proof-of-concept, we aimed to delineate the low-expressing complement receptor 1 (CR1) Helgeson phenotype on erythrocytes, which is correlated with several diseases and protects against severe malaria. We demonstrate that two candidate CR1 enhancer motifs in intron 4 bind GATA1 and drive transcription. Both are functionally abolished by naturally-occurring SNVs. Erythrocyte CR1-mRNA and CR1 levels... (More)

Genetic determinants underlying most human blood groups are now clarified but variation in expression levels remains largely unexplored. By developing a bioinformatics pipeline analyzing GATA1/Chromatin immunoprecipitation followed by sequencing (ChIP-seq) datasets, we identify 193 potential regulatory sites in 33 blood-group genes. As proof-of-concept, we aimed to delineate the low-expressing complement receptor 1 (CR1) Helgeson phenotype on erythrocytes, which is correlated with several diseases and protects against severe malaria. We demonstrate that two candidate CR1 enhancer motifs in intron 4 bind GATA1 and drive transcription. Both are functionally abolished by naturally-occurring SNVs. Erythrocyte CR1-mRNA and CR1 levels correlate dose-dependently with genotype of one SNV (rs11117991) in two healthy donor cohorts. Haplotype analysis of rs11117991 with previously proposed markers for Helgeson shows high linkage disequilibrium in Europeans but explains the poor prediction reported for Africans. These data resolve the longstanding debate on the genetic basis of inherited low CR1 and form a systematic starting point to investigate the blood group regulome.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Phenotype, Genotype, Introns, African People, Computational Biology, GATA1 Transcription Factor/genetics, Receptors, Complement 3b
in
Nature Communications
volume
14
issue
1
article number
5001
publisher
Nature Publishing Group
external identifiers
  • scopus:85168273151
  • pmid:37591894
ISSN
2041-1723
DOI
10.1038/s41467-023-40708-w
project
The blood group regulome project
language
English
LU publication?
yes
additional info
© 2023. Springer Nature Limited.
id
d1a86917-481d-4b64-be1c-c142764f8a76
date added to LUP
2023-08-29 09:15:07
date last changed
2024-04-20 02:08:39
@article{d1a86917-481d-4b64-be1c-c142764f8a76,
  abstract     = {{<p>Genetic determinants underlying most human blood groups are now clarified but variation in expression levels remains largely unexplored. By developing a bioinformatics pipeline analyzing GATA1/Chromatin immunoprecipitation followed by sequencing (ChIP-seq) datasets, we identify 193 potential regulatory sites in 33 blood-group genes. As proof-of-concept, we aimed to delineate the low-expressing complement receptor 1 (CR1) Helgeson phenotype on erythrocytes, which is correlated with several diseases and protects against severe malaria. We demonstrate that two candidate CR1 enhancer motifs in intron 4 bind GATA1 and drive transcription. Both are functionally abolished by naturally-occurring SNVs. Erythrocyte CR1-mRNA and CR1 levels correlate dose-dependently with genotype of one SNV (rs11117991) in two healthy donor cohorts. Haplotype analysis of rs11117991 with previously proposed markers for Helgeson shows high linkage disequilibrium in Europeans but explains the poor prediction reported for Africans. These data resolve the longstanding debate on the genetic basis of inherited low CR1 and form a systematic starting point to investigate the blood group regulome.</p>}},
  author       = {{Wu, Ping Chun and Lee, Yan Quan and Möller, Mattias and Storry, Jill R and Olsson, Martin L}},
  issn         = {{2041-1723}},
  keywords     = {{Humans; Phenotype; Genotype; Introns; African People; Computational Biology; GATA1 Transcription Factor/genetics; Receptors, Complement 3b}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Elucidation of the low-expressing erythroid CR1 phenotype by bioinformatic mining of the GATA1-driven blood-group regulome}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-40708-w}},
  doi          = {{10.1038/s41467-023-40708-w}},
  volume       = {{14}},
  year         = {{2023}},
}