Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner

Holik, Aliaksei Z.; Krzystyniak, Joanna; Young, Madeleine A.; Richardson, Kirsty; Jardé, Thierry; Chambon, Pierre; Shorning, Boris; Clarke, Alan R.

doi:10.1002/stem.1498

Cited by 35 publications

(36 citation statements)

References 48 publications

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“…This finding is consistent with a previous report showing that Notch inhibition by conditional knockout of Hes1, Hes3 or Hes5 results in increased apoptosis in murine intestinal epithelial cells (Ueo et al, 2012). A previous study shows that apoptotic cells are increased only in crypt lesions in adult Brg1 mutant mice (Holik et al, 2013). Similarly, crypt-restricted apoptosis increased in the adult Notch inactivation models (Milano et al, 2004).…”

Section: Discussionsupporting

confidence: 93%

“…Brg1 is essential for maintenance of intestinal stem cells (Holik et al, 2013). To investigate the effect of loss of Brg1 on the development of intestinal stem cells, we used Lgr5-GFP mice, in which Lgr5 + CBC cells are GFP positive (Barker et al, 2007).…”

Section: Loss Of Brg1 Results In Depletion Of Intestinal Stem Cellsmentioning

confidence: 99%

“…Brg1 is essential for intestinal stem cell homeostasis (Holik et al, 2013), but the molecular details of the requirement for Brg1 in intestinal stem cell maintenance remain unknown. Notch signaling is essential for survival of intestinal stem cells (Pellegrinet et al, 2011;VanDussen et al, 2012) and treatment with the Notch inhibitor DBZ causes intestinal stem cell loss (VanDussen et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies showed that Brg1 is essential for development or homeostasis of various organs and cell types, including heart (Hang et al, 2010;Takeuchi et al, 2011), vasculature (Davis et al, 2013;Griffin et al, 2008Griffin et al, , 2011, ureter (Weiss et al, 2013), smooth muscle (Zhang et al, 2011) and neurons (Li et al, 2013;Matsumoto et al, 2006;Seo et al, 2005). In the intestine, Brg1 is essential for maintenance of intestinal stem cells (Holik et al, 2013). However, the functional role of Brg1 in intestinal development and homeostasis and its molecular mechanism remain to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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97 BRG1 Plays an Essential Role in Development and Homeostasis of the Duodenum Through Regulation of Notch Signaling

Takada¹,

Fukuda²,

Chiba³

et al. 2016

Gastroenterology

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Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt-villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum. Furthermore, we found that the Notch signaling pathway was dramatically downregulated in Brg1-deficient duodenum. Remarkably, overexpression of the Notch1 intercellular domain (ICD) partially reversed the prognosis of intestinal Brg1 mutant mice. Notch1 ICD overexpression rescued morphogenesis, prevented over-differentiation into secretory lineage cells, and restored apoptosis to normal levels in Brg1-deficient duodenum, although stem cell loss was not rescued. Our data demonstrate that Brg1 plays an essential role in development and homeostasis, including morphogenesis, stem cell differentiation and cell survival in the duodenum. Mechanistically, the rescue of the intestinal Brg1 mutant phenotype by overexpression of the Notch1 ICD indicates that Notch signaling is a key downstream target that mediates the effects of Brg1.

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Section: Discussionsupporting

confidence: 93%

Section: Loss Of Brg1 Results In Depletion Of Intestinal Stem Cellsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

97 BRG1 Plays an Essential Role in Development and Homeostasis of the Duodenum Through Regulation of Notch Signaling

Takada¹,

Fukuda²,

Chiba³

et al. 2016

Gastroenterology

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“…Cdx and Brg1 Interact in Vivo-Cdx and SWI-SNF impact intestinal differentiation programs and are required for maintenance of the intestinal stem cell niche (7,11,44). To determine whether Cdx and Brg1 interacted genetically in this context, we assessed intestinal cell differentiation using differential staining for enterocytes and goblet and enteroendocrine cells, comparing control Cdx1 (Fig.…”

Section: Cdx2 and Brg1 Impact The Chromatin Architecture At CDXmentioning

confidence: 99%

Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch-Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity

Nguyen

Savory

Brooke-Bisschop

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuThe packaging of genomic DNA into nucleosomes creates a barrier to transcription that can be relieved through ATP-dependent chromatin remodeling via complexes such as the switch-sucrose non-fermentable (SWI-SNF) chromatin remodeling complex. The SWI-SNF complex remodels chromatin via conformational or positional changes of nucleosomes, thereby altering the access of transcriptional machinery to target genes. The SWI-SNF complex has limited ability to bind to sequencespecific elements, and, therefore, its recruitment to target loci is believed to require interaction with DNA-associated transcription factors. The Cdx family of homeodomain transcript ion factors (Cdx1, Cdx2, and Cdx4) are essential for a number of developmental programs in the mouse. Cdx1 and Cdx2 also regulate intestinal homeostasis throughout life. Although a number of Cdx target genes have been identified, the basis by which Cdx members impact their transcription is poorly understood. We have found that Cdx members interact with the SWI-SNF complex and make direct contact with Brg1, a catalytic member of SWI-SNF. Both Cdx2 and Brg1 co-occupy a number of Cdx target genes, and both factors are necessary for transcriptional regulation of such targets. Finally, Cdx2 and Brg1 occupancy occurs coincident with chromatin remodeling at some of these loci. Taken together, our findings suggest that Cdx transcription factors regulate target gene expression, in part, through recruitment of Brg1-associated SWI-SNF chromatin remodeling activity.The Cdx genes are vertebrate orthologs of Drosophila caudal and encode homeodomain transcriptional factors. In the mouse, the three members of this family (Cdx1, Cdx2, and Cdx4) are co-expressed in the caudal embryo in all three germ layers commencing at mid-gastrulation and play overlapping roles in a number of developmental programs, including axial elongation, endoderm specification, and anterior-posterior vertebral patterning (1-6). Both Cdx1 and Cdx2 are also expressed in the intestinal epithelium throughout life, where they play critical roles in intestinal homeostasis (7-11) and can function as tumor suppressors (12-15). Although Cdx members play critical roles in governing gene expression during development and in the adult intestine, little is known about the mechanisms by which Cdx members regulate target gene transcription.The packaging of DNA into nucleosomes creates a barrier to transcription by obstructing access of the basal transcription machinery as well as modulating access of other transcriptional regulators to their DNA binding motifs (16 -19). Alteration of the chromatin structure by ATP-dependent remodeling complexes can alleviate these constraints, and such complexes play important roles in the transcriptional regulation of many eukaryotic genes. Such complexes include the switch-sucrose non-fermentable (SWI-SNF) 2 chromatin-remodeling complex (16, 20 -22), which remodels the chromatin structure via conformational or positional changes of nucleosomes (23,24). Because the SWI-...

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Brahma‐Related Gene 1 Inhibition Prevents Liver Fibrosis and Cholangiocarcinoma by Attenuating Progenitor Expansion

et al. 2021

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BaCKgRoUND aND aIMS:Intrahepatic cholangiocarcinoma (iCCA) is closely correlated with hepatic progenitor cell (HPC) expansion and liver fibrosis. Brahmarelated gene 1 (Brg1), an enzymatic subunit of the switch/ sucrose nonfermentable complex that is critical in stem cell maintenance and tumor promotion, is prominently upregulated in both HPCs and iCCA; however, its role in this correlation remains undefined. appRoaCH aND ReSUltS: A retrospective cohort study indicated that high Brg1 expression suggests poor prognosis in patients with iCCA. In chronically injured livers induced by a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet or bile duct ligation surgery, HPCs were dramatically activated, as indicated by their enhanced expression of Brg1 and a subset of stem cell markers; however, Brg1 ablation in HPCs strongly suppressed HPC expansion and liver fibrosis. Furthermore, in a chemically induced iCCA model, inhibition of Brg1 by a specific inhibitor or inducible gene ablation markedly improved histology and suppressed iCCA growth. Mechanistically, in addition to transcriptionally promoting both Wnt receptor genes and target genes, Brg1 was found to bind to the β-catenin/transcription factor 4 transcription complex, suggesting a possible approach for regulation of Wnt/β-catenin signaling. CoNClUSIoNS:We have demonstrated the function of Brg1 in promoting HPC expansion, liver cirrhosis, and, ultimately, iCCA development in chronically injured livers, which is largely dependent on Wnt/β-catenin signaling. Our data suggest that therapies targeting Brg1-expressing HPCs are promising for the treatment of liver cirrhosis and iCCA.

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Brg1 is required for stem cell maintenance in the murine intestinal epithelium in a tissue-specific manner

Cited by 35 publications

References 48 publications

97 BRG1 Plays an Essential Role in Development and Homeostasis of the Duodenum Through Regulation of Notch Signaling

97 BRG1 Plays an Essential Role in Development and Homeostasis of the Duodenum Through Regulation of Notch Signaling

Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch-Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity

Brahma‐Related Gene 1 Inhibition Prevents Liver Fibrosis and Cholangiocarcinoma by Attenuating Progenitor Expansion

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