Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

Huiling Xu; Yuqian Yan; Siddhartha Deb; Danny Rangasamy; Markus Germann; Jordane Malaterre; Noreen C. Eder; Robyn L. Ward; Nicholas J. Hawkins; Richard W. Tothill; Long Chen; Neil J. Mortensen; Stephen B. Fox; Michael J. McKay; Robert G. Ramsay

doi:10.1016/j.celrep.2014.10.059

Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

Huiling Xu, Yuqian Yan, Siddhartha Deb, Danny Rangasamy, Markus Germann, Jordane Malaterre, Noreen C. Eder, Robyn L. Ward, Nicholas J. Hawkins, Richard W. Tothill, Long Chen, Neil J. Mortensen, Stephen B. Fox, Michael J. McKay, Robert G. Ramsay^*

^*Corresponding author for this work

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

40 Citations (Scopus)

Abstract

Loss of heterozygosity (LOH) of the adenomatous polyposis coli (. APC) gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC). We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1) retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer. Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu etal. identify Rad21 as a key mediator of Apc gene heterozygous loss, the event initiating intestinal tumorigenesis. The subsequent activation of the Wnt pathway further induces Rad21, global gene dysregulation, chromosome instability, and pervasive retrotransposon activation.

Original language	English
Pages (from-to)	1781-1797
Number of pages	17
Journal	Cell Reports
Volume	9
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2014.10.059
Publication status	Published - 11 Dec 2014

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Xu, H., Yan, Y., Deb, S., Rangasamy, D., Germann, M., Malaterre, J., Eder, N. C., Ward, R. L., Hawkins, N. J., Tothill, R. W., Chen, L., Mortensen, N. J., Fox, S. B., McKay, M. J., & Ramsay, R. G. (2014). Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors. Cell Reports, 9(5), 1781-1797. https://doi.org/10.1016/j.celrep.2014.10.059

@article{b8cbf39f69e04290b311e795bdb3440b,

title = "Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors",

abstract = "Loss of heterozygosity (LOH) of the adenomatous polyposis coli (. APC) gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC). We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1) retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer. Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu etal. identify Rad21 as a key mediator of Apc gene heterozygous loss, the event initiating intestinal tumorigenesis. The subsequent activation of the Wnt pathway further induces Rad21, global gene dysregulation, chromosome instability, and pervasive retrotransposon activation.",

author = "Huiling Xu and Yuqian Yan and Siddhartha Deb and Danny Rangasamy and Markus Germann and Jordane Malaterre and Eder, {Noreen C.} and Ward, {Robyn L.} and Hawkins, {Nicholas J.} and Tothill, {Richard W.} and Long Chen and Mortensen, {Neil J.} and Fox, {Stephen B.} and McKay, {Michael J.} and Ramsay, {Robert G.}",

note = "Publisher Copyright: {\textcopyright} 2014 The Authors.",

year = "2014",

month = dec,

day = "11",

doi = "10.1016/j.celrep.2014.10.059",

language = "English",

volume = "9",

pages = "1781--1797",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier B.V.",

number = "5",

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Xu, H, Yan, Y, Deb, S, Rangasamy, D, Germann, M, Malaterre, J, Eder, NC, Ward, RL, Hawkins, NJ, Tothill, RW, Chen, L, Mortensen, NJ, Fox, SB, McKay, MJ & Ramsay, RG 2014, 'Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors', Cell Reports, vol. 9, no. 5, pp. 1781-1797. https://doi.org/10.1016/j.celrep.2014.10.059

TY - JOUR

T1 - Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

AU - Xu, Huiling

AU - Yan, Yuqian

AU - Deb, Siddhartha

AU - Rangasamy, Danny

AU - Germann, Markus

AU - Malaterre, Jordane

AU - Eder, Noreen C.

AU - Ward, Robyn L.

AU - Hawkins, Nicholas J.

AU - Tothill, Richard W.

AU - Chen, Long

AU - Mortensen, Neil J.

AU - Fox, Stephen B.

AU - McKay, Michael J.

AU - Ramsay, Robert G.

PY - 2014/12/11

Y1 - 2014/12/11

N2 - Loss of heterozygosity (LOH) of the adenomatous polyposis coli (. APC) gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC). We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1) retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer. Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu etal. identify Rad21 as a key mediator of Apc gene heterozygous loss, the event initiating intestinal tumorigenesis. The subsequent activation of the Wnt pathway further induces Rad21, global gene dysregulation, chromosome instability, and pervasive retrotransposon activation.

AB - Loss of heterozygosity (LOH) of the adenomatous polyposis coli (. APC) gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC). We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1) retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer. Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu etal. identify Rad21 as a key mediator of Apc gene heterozygous loss, the event initiating intestinal tumorigenesis. The subsequent activation of the Wnt pathway further induces Rad21, global gene dysregulation, chromosome instability, and pervasive retrotransposon activation.

UR - http://www.scopus.com/inward/record.url?scp=84915821343&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2014.10.059

DO - 10.1016/j.celrep.2014.10.059

M3 - Article

SN - 2211-1247

VL - 9

SP - 1781

EP - 1797

JO - Cell Reports

JF - Cell Reports

IS - 5

ER -

Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

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