Chromatin remodelling ATPase Brg-1 is an essential factor for the maintenance of the intestinal crypt stem cell and adenoma formation Aliaksei Holik.

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Chromatin remodelling ATPase Brg-1 is an essential factor for the maintenance of the intestinal crypt stem cell and adenoma formation Aliaksei Holik

BRG-1 and cancer BRG-1 mutations are found in human cancer cell lines and in primary cancers Heterozygous deletion of Brg-1 in mice promotes tumourigenesis via Brg-1 haploinsufficiency Restoration of BRG-1 function leads to the reversion of a cancer phenotype

Suggested mechanisms of BRG1 role in tumourigenesis p53 BRCA1 RB/p21 BRG-1 c-Fos Wnt-pathway

Wnt pathway Willert K., Jones K. A. Genes Dev. 2006;20:1394-1404

Small intestine architecture Villus Transit amplifying cells Crypt Stem cell

Generation of conditional knock-out using Cre-loxP techniques loxP strategy

Brg-1-deficient cells in small intestine are repopulated with wild-type cells AhCre-ERT BRG-1 Day 3 Day 5 Day 7

Brg-1-deficient small intestinal epithelium appears to be normal at day 4 post induction Control BRG-1 Brg1fl/fl VillinCre-ERT

Brg1-deficient small intestinal epithelium displays no difference in mitosis and apoptosis levels VillinCre-Brg1fl/fl VillinCre+Brg1fl/fl p-values: Mitosis – 0.629 Apoptosis – 0.057

Brg1-deficient small intestinal epithelium displays no difference in mitosis and apoptosis levels VillinCre-Brg1fl/fl VillinCre+Brg1fl/fl

Inactivation of Brg-1 in small intestinal epithelium leads to rapid crypt loss Control Day 4 Day 5 Day 7 Brg1fl/fl

Brg-1 loss leads to the failure of the crypt stem cell Transit amplifying cells Active stem cell

Loss of Brg-1 results in reduced expression of intestinal stem cell markers VillinCre-Brg1fl/fl VillinCre+Brg1fl/fl p-value < 0.05

Generation of double knock-out using Cre-loxP techniques

Brg-1/Apc double mutant cells are selectively eliminated in small intestine -catenin BRG-1 Small intestine of Brg1fl/fl/Apcfl/fl mouse at day 7 post induction

Median survival Apcfl/fl=8 Brg1fl/flApcfl/fl=14, P=0.0010 Brg-1-deficiency rescues lethal phenotype of Apc deletion in double knock-out mice Control Brg1fl/flApcfl/fl Apcfl/fl Brg1fl/fl Median survival Apcfl/fl=8 Brg1fl/flApcfl/fl=14, P=0.0010

Brg-1 deletion removes a portion of Apc-deficient cells decreasing tumour burden Brg1-/Apc-

Brg-1 deletion removes a portion of Apc-deficient cells decreasing tumour burden Brg1-/Apc-

Adenoma progression depends on the cell of origin Microadenoma Transit amplifying cells Stem cell Adenoma

Conclusions Brg-1 is a crucial factor for the maintenance of the adult tissue stem cell in small intestine. Brg-1 loss is incompatible with activation of the Wnt pathway in the murine small intestine Targeting the intestinal stem cell provides an attractive concept for the removal of potentially malignant lesions in individuals with genetic predisposition to colorectal cancer

Acknowledgements The Darwin Trust of Edinburgh Alan Clarke Boris Shorning ARC group