Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2

Vidya Rajasekaran-Sutherland; Bradley T Harris; Ruby T Osborn; Claire Smillie; Kevin Donnelly; Marion Bacou; Edward Esiri-Bloom; Li-Yin Ooi; Morven Allan; Marion Walker; Stuart Reid; Alison Meynert; Graeme Grimes; James P Blackmur; Peter G Vaughan-Shaw; Philip J Law; Ceres Fernandez-Rozadilla; Ian Tomlinson; Richard S Houlston; Kevin B Myant; Farhat VN Din; Maria Timofeeva; Malcolm G Dunlop; Susan M Farrington

doi:10.1136/gutjnl-2024-332121

Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2

Vidya Rajasekaran-Sutherland, Bradley T Harris, Ruby T Osborn, Claire Smillie, Kevin Donnelly, Marion Bacou, Edward Esiri-Bloom, Li-Yin Ooi, Morven Allan, Marion Walker, Stuart Reid, Alison Meynert, Graeme Grimes, James P Blackmur, Peter G Vaughan-Shaw, Philip J Law, Ceres Fernandez-Rozadilla, Ian Tomlinson, Richard S Houlston, Kevin B MyantFarhat VN Din, Maria Timofeeva, Malcolm G Dunlop, Susan M Farrington

Research output: Contribution to journal › Article › peer-review

Abstract

Background:
Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on POU2AF2, COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk.

Objective
Undertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk.

Design:
We employ analysis of RNAseq, scRNAseq, ChIPseq and scATACseq data to identify, prioritise and characterise the genes which impart CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa.

Results:
We establish rs3087967 as a prime eQTL variant at 11q23.1, co-localising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the ApcMin/+ mouse phenotype upon abrogation of Pou2af2 expression specifically.

Conclusion:
We demonstrate that genotype at rs3087967 controls a portfolio of genes through mis-regulation of POU2AF2. POU2AF2 is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium.

Original language	English
Pages (from-to)	787-803
Journal	Gut
Volume	74
Issue number	5
Early online date	28 Nov 2024
DOIs	https://doi.org/10.1136/gutjnl-2024-332121
Publication status	Published - 7 Apr 2025

Keywords / Materials (for Non-textual outputs)

colorectal
risk
single-cell
transcriptomics
accessibility
WGCNA
mouse-models
tuft cells
POU2AF2
POU2AF3
POU2F3

Access to Document

10.1136/gutjnl-2024-332121

Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2_finalFinal published version, 11.8 MBLicence: Creative Commons: Attribution (CC-BY)

CRUK Edinburgh Centre Clinical Fellowship
Frame, M. (Principal Investigator)
UK-based charities
1/02/17 → 31/01/20
Project: Research
Investigation of gene-environment interactions between Vitamin D and colorectal cancer susceptibility genetic variants in large bowel epithelium.
Vaughan-Shaw, P. (Principal Investigator)
MRC
1/02/15 → 1/02/17
Project: Research
Dissecting the Genetics of Colorectal Cancer: New Quinque
Dunlop, M. (Principal Investigator)
UK-based charities
1/01/11 → 31/12/15
Project: Research

Bioinformatics Analysis Core
Meynert, A. (Manager), Wham, M. (Other), Donnelly, K. (Other), Halachev, M. (Other), Becher, H. (Other), Gautier, P. (Other) & Grimes, G. (Other)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

Rajasekaran-Sutherland, V., Harris, B. T., Osborn, R. T., Smillie, C., Donnelly, K., Bacou, M., Esiri-Bloom, E., Ooi, L.-Y., Allan, M., Walker, M., Reid, S., Meynert, A., Grimes, G., Blackmur, J. P., Vaughan-Shaw, P. G., Law, P. J., Fernandez-Rozadilla, C., Tomlinson, I., Houlston, R. S., ... Farrington, S. M. (2025). Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2. Gut, 74(5), 787-803. https://doi.org/10.1136/gutjnl-2024-332121

@article{3d6cb5c233db492cb02829a8525d1e43,

title = "Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2",

abstract = "Background:Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on POU2AF2, COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk. ObjectiveUndertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk.Design:We employ analysis of RNAseq, scRNAseq, ChIPseq and scATACseq data to identify, prioritise and characterise the genes which impart CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa.Results:We establish rs3087967 as a prime eQTL variant at 11q23.1, co-localising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the ApcMin/+ mouse phenotype upon abrogation of Pou2af2 expression specifically. Conclusion:We demonstrate that genotype at rs3087967 controls a portfolio of genes through mis-regulation of POU2AF2. POU2AF2 is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium.",

keywords = "colorectal, risk, single-cell, transcriptomics, accessibility, WGCNA, mouse-models, tuft cells, POU2AF2, POU2AF3, POU2F3",

author = "Vidya Rajasekaran-Sutherland and Harris, {Bradley T} and Osborn, {Ruby T} and Claire Smillie and Kevin Donnelly and Marion Bacou and Edward Esiri-Bloom and Li-Yin Ooi and Morven Allan and Marion Walker and Stuart Reid and Alison Meynert and Graeme Grimes and Blackmur, {James P} and Vaughan-Shaw, {Peter G} and Law, {Philip J} and Ceres Fernandez-Rozadilla and Ian Tomlinson and Houlston, {Richard S} and Myant, {Kevin B} and Din, {Farhat VN} and Maria Timofeeva and Dunlop, {Malcolm G} and Farrington, {Susan M}",

year = "2025",

month = apr,

day = "7",

doi = "10.1136/gutjnl-2024-332121",

language = "English",

volume = "74",

pages = "787--803",

journal = "Gut",

issn = "0017-5749",

publisher = "BMJ Publishing Group",

number = "5",

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Rajasekaran-Sutherland, V, Harris, BT, Osborn, RT, Smillie, C, Donnelly, K, Bacou, M, Esiri-Bloom, E, Ooi, L-Y, Allan, M , Walker, M, Reid, S, Meynert, A, Grimes, G, Blackmur, JP, Vaughan-Shaw, PG, Law, PJ, Fernandez-Rozadilla, C, Tomlinson, I, Houlston, RS, Myant, KB , Din, FVN, Timofeeva, M, Dunlop, MG & Farrington, SM 2025, 'Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2', Gut, vol. 74, no. 5, pp. 787-803. https://doi.org/10.1136/gutjnl-2024-332121

TY - JOUR

T1 - Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2

AU - Rajasekaran-Sutherland, Vidya

AU - Harris, Bradley T

AU - Osborn, Ruby T

AU - Smillie, Claire

AU - Donnelly, Kevin

AU - Bacou, Marion

AU - Esiri-Bloom, Edward

AU - Ooi, Li-Yin

AU - Allan, Morven

AU - Walker, Marion

AU - Reid, Stuart

AU - Meynert, Alison

AU - Grimes, Graeme

AU - Blackmur, James P

AU - Vaughan-Shaw, Peter G

AU - Law, Philip J

AU - Fernandez-Rozadilla, Ceres

AU - Tomlinson, Ian

AU - Houlston, Richard S

AU - Myant, Kevin B

AU - Din, Farhat VN

AU - Timofeeva, Maria

AU - Dunlop, Malcolm G

AU - Farrington, Susan M

PY - 2025/4/7

Y1 - 2025/4/7

N2 - Background:Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on POU2AF2, COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk. ObjectiveUndertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk.Design:We employ analysis of RNAseq, scRNAseq, ChIPseq and scATACseq data to identify, prioritise and characterise the genes which impart CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa.Results:We establish rs3087967 as a prime eQTL variant at 11q23.1, co-localising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the ApcMin/+ mouse phenotype upon abrogation of Pou2af2 expression specifically. Conclusion:We demonstrate that genotype at rs3087967 controls a portfolio of genes through mis-regulation of POU2AF2. POU2AF2 is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium.

AB - Background:Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, exerting local expression quantitative trait locus (cis-eQTL) effects on POU2AF2, COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression has hindered elucidation of the mechanisms by which genetic variants impart underlying CRC risk. ObjectiveUndertake an interdisciplinary approach to understand how variation at 11q23.1 locus imparts CRC risk.Design:We employ analysis of RNAseq, scRNAseq, ChIPseq and scATACseq data to identify, prioritise and characterise the genes which impart CRC risk. We further validate these findings using mouse models and demonstrate parallel effects in human colonic mucosa.Results:We establish rs3087967 as a prime eQTL variant at 11q23.1, co-localising with CRC risk. Furthermore, rs3087967 influences expression of 21 distant genes, thereby acting as a trans-eQTL hub for a gene-set highly enriched for tuft cell markers. Epigenomic analysis implicates POU2AF2 as controlling the tuft cell specific trans-genes, through POU2F3-correlated genomic regulation. Immunofluorescence confirms rs3087967 risk genotype (T) to be associated with a tuft cell deficit in the human colon. CRISPR-mediated deletion of the 11q23.1 risk locus genes in the mouse germline exacerbated the ApcMin/+ mouse phenotype upon abrogation of Pou2af2 expression specifically. Conclusion:We demonstrate that genotype at rs3087967 controls a portfolio of genes through mis-regulation of POU2AF2. POU2AF2 is the primary transcriptional activator of tuft cells with a tumour suppressive role in mouse models. We therefore implicate tuft cells as having a key tumour-protective role in the large bowel epithelium.

KW - colorectal

KW - risk

KW - single-cell

KW - transcriptomics

KW - accessibility

KW - WGCNA

KW - mouse-models

KW - tuft cells

KW - POU2AF2

KW - POU2AF3

KW - POU2F3

U2 - 10.1136/gutjnl-2024-332121

DO - 10.1136/gutjnl-2024-332121

M3 - Article

SN - 0017-5749

VL - 74

SP - 787

EP - 803

JO - Gut

JF - Gut

IS - 5

ER -

Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activator – POU2AF2

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

CRUK Edinburgh Centre Clinical Fellowship

Investigation of gene-environment interactions between Vitamin D and colorectal cancer susceptibility genetic variants in large bowel epithelium.

Dissecting the Genetics of Colorectal Cancer: New Quinque

Equipment

Bioinformatics Analysis Core

Cite this