Chromatin remodeling mediated by the FOXA1/A2 transcription factors activates<i>CFTR</i>expression in intestinal epithelial cells

Kerschner, Jenny L.; Gosalia, Nehal; Leir, Shih Hsing; Harris, Ann

doi:10.4161/epi.27696

Cited by 48 publications

(50 citation statements)

References 41 publications

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“…FOXA2 has been described as a transcriptional activator for AFP and albumin (ALB) and regulator of lipid metabolism and fibrinogens [25–27]. Furthermore, FOXA2 is involved in development of endodermal-derived organs like the liver, pancreas and lungs [28, 29].…”

Section: Resultsmentioning

confidence: 99%

SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

et al. 2016

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Type II germ cell cancers (GCC) are divided into seminomas, which are highly similar to primordial germ cells and embryonal carcinomas (EC), often described as malignant counterparts to embryonic stem cells.Previously, we demonstrated that the development of GCCs is a highly plastic process and strongly influenced by the microenvironment. While orthotopic transplantation into the testis promotes seminomatous growth of the seminoma-like cell line TCam-2, ectopic xenotransplantation into the flank initiates reprogramming into an EC-like fate.During this reprogramming, BMP signaling is inhibited, leading to induction of NODAL signaling, upregulation of pluripotency factors and downregulation of seminoma markers, like SOX17. The pluripotency factor and EC-marker SOX2 is strongly induced.Here, we adressed the molecular role of SOX2 in this reprogramming. Using CRISPR/Cas9-mediated genome-editing, we established SOX2-deficient TCam-2 cells. Xenografting of SOX2-deficient cells into the flank of nude mice resulted in maintenance of a seminoma-like fate, indicated by the histology and expression of OCT3/4, SOX17, TFAP2C, PRDM1 and PRAME. In SOX2-deficient cells, BMP signaling is inhibited, but NODAL signaling is not activated. Thus, SOX2 appears to be downstream of BMP signaling but upstream of NODAL activation. So, SOX2 is an essential factor in acquiring an EC-like cell fate from seminomas.A small population of differentiated cells was identified resembling a mixed non-seminoma. Analyses of these cells revealed downregulation of the pluripotency and seminoma markers OCT3/4, SOX17, PRDM1 and TFAP2C. In contrast, the pioneer factor FOXA2 and its target genes were upregulated, suggesting that FOXA2 might play an important role in induction of non-seminomatous differentiation.

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Section: Resultsmentioning

confidence: 99%

SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

et al. 2016

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“…The SNP in the 7p15.2 region most highly associated with prostate cancer risk (rs10486567) is within a motif for AR-FOXA1 and NKX3.1; these factors have been shown to bind to this region in LNCaP prostate cancer cells (Tan et al, 2012). FOXA1 is a pioneer factor that can localize to nucleosome-bound chromatin and serve as a repressor (Bernardo et al, 2013; Lupien et al, 2008); previous studies have shown that FOXA1 is a critical component of a long-range loop (Kerschner et al, 2014). Thus, one possible mechanism by which the 7p15.2 risk region could mediate long-range repression is via formation of a FOXA1-mediated repressive loop.…”

Section: Discussionmentioning

confidence: 99%

A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13

et al. 2017

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Summary Prostate cancer (PCa) is the leading cancer among men in the United States, with genetic factors contributing to ~42% of the susceptibility to PCa. We analyzed a PCa risk region located at 7p15.2 to gain insight into the mechanisms by which this noncoding region may affect gene regulation and contribute to PCa risk. We performed Hi-C analysis and demonstrated that this region has long range interactions with the HOXA locus, located ~873 kb away. Using the CRISPR/Cas9 system, we deleted a 4kb region encompassing several prostate cancer risk-associated SNPs and performed RNA-seq to investigate transcriptomic changes in prostate cells lacking the regulatory element. Our results suggest that the risk element affects the expression of HOXA13 and HOTTIP, but not other genes in the HOXA locus, via a repressive loop. Forced expression of HOXA13 was performed to gain further insight into the mechanisms by which this risk element affects PCa risk.

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“…Chromatin structures that facilitate long-range interactions between various regulatory elements cluster specifically to the CFTR promoter exclusively in CFTR expressing cells [25,26]. Recently, it was reported that trans-interacting Forkhead Box A (FOXA) factors induce CFTR activation through binding to a key CFTR cis-regulatory element located in introns 10 and 11 [27][28][29]. CFTR expression is post-transcriptionally regulated also by miRNAs, such as miR-145 and miR-494 [30][31][32].…”

Section: Introductionmentioning

confidence: 99%

Transcription factors and miRNAs that regulate fetal to adultCFTRexpression change are new targets for cystic fibrosis

Viart¹,

Bergougnoux²,

Bonini³

et al. 2014

Eur Respir J

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The CFTR gene displays a tightly regulated tissue-specific and temporal expression. Mutations in this gene cause cystic fibrosis (CF). In this study we wanted to identify trans-regulatory elements responsible for CFTR differential expression in fetal and adult lung, and to determine the importance of inhibitory motifs in the CFTR-3′UTR with the aim of developing new tools for the correction of disease-causing mutations within CFTR.We show that lung development-specific transcription factors (FOXA, C/EBP) and microRNAs (miR-101, miR-145, miR-384) regulate the switch from strong fetal to very low CFTR expression after birth. By using miRNome profiling and gene reporter assays, we found that miR-101 and miR-145 are specifically upregulated in adult lung and that miR-101 directly acts on its cognate site in the CFTR-3′UTR in combination with an overlapping AU-rich element. We then designed miRNA-binding blocker oligonucleotides (MBBOs) to prevent binding of several miRNAs to the CFTR-3′UTR and tested them in primary human nasal epithelial cells from healthy individuals and CF patients carrying the p.Phe508del CFTR mutation. These MBBOs rescued CFTR channel activity by increasing CFTR mRNA and protein levels.Our data offer new understanding of the control of the CFTR gene regulation and new putative correctors for cystic fibrosis. @ERSpublications Transcription factors/miRNAs that regulate fetal to adult CFTR expression change are new targets for CF treatment

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Chromatin remodeling mediated by the FOXA1/A2 transcription factors activatesCFTRexpression in intestinal epithelial cells

Cited by 48 publications

References 41 publications

SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

SOX2 is essential for in vivo reprogramming of seminoma-like TCam-2 cells to an embryonal carcinoma-like fate

A Prostate Cancer Risk Element Functions as a Repressive Loop that Regulates HOXA13

Transcription factors and miRNAs that regulate fetal to adultCFTRexpression change are new targets for cystic fibrosis

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