Identification of novel human Wnt target genes using adult endodermal tissue-derived organoids

Boonekamp, Kim E.; Heo, Inha; Artegiani, Benedetta; Asra, Priyanca; Son, Gijs van; Ligt, Joep de

doi:10.1016/j.ydbio.2021.01.009

Cited by 29 publications

(20 citation statements)

References 47 publications

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“…Aside from the genes linked to the GO term Cell Proliferation, we examined our DEG list for changes in Wnt and β-catenin ( Ctnnb1 ) gene expression but did not observe any changes suggesting that they are not direct transcriptional targets of Snf2l ( Figure 3C and Supplementary Table 1 ). Comparison of our DEG list with known direct and indirect Wnt target genes from two sources (The Wnt Homepage; Boonekamp et al, 2021 ) revealed increased expression in seven additional Wnt target genes ( Abcb1a , Log 2 FC = 0.97; Neurod1 , Log 2 FC = –0.61; Ptgs2 , Log 2 FC = 0.89; Fn1 , Log 2 FC = 0.77; and Plaur , Log 2 FC = 1.12; Abcc4 , Log 2 FC = 0.74; Nes , Log 2 FC = 0.63) suggesting activation of the Wnt signaling cascade in Ex6DEL cultures. Moreover, several downstream signaling components of the Edn1/Ednra pathway showed increased expression including Mapk15 (Log 2 FC = 0.87), Map3k8 (Log 2 FC = 0.61), and Fos gene expression ( Fosb , Log 2 FC = 0.64; Fosl2 , Log 2 FC = 0.74) suggesting further involvement of this effector pathway ( Supplementary Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation

Goodwin

Zapata

Timpano

et al. 2021

Front. Mol. Neurosci.

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Chromatin remodeling proteins utilize the energy from ATP hydrolysis to mobilize nucleosomes often creating accessibility for transcription factors within gene regulatory elements. Aberrant chromatin remodeling has diverse effects on neuroprogenitor homeostasis altering progenitor competence, proliferation, survival, or cell fate. Previous work has shown that inactivation of the ISWI genes, Smarca5 (encoding Snf2h) and Smarca1 (encoding Snf2l) have dramatic effects on brain development. Smarca5 conditional knockout mice have reduced progenitor expansion and severe forebrain hypoplasia, with a similar effect on the postnatal growth of the cerebellum. In contrast, Smarca1 mutants exhibited enlarged forebrains with delayed progenitor differentiation and increased neuronal output. Here, we utilized cerebellar granule neuron precursor (GNP) cultures from Smarca1 mutant mice (Ex6DEL) to explore the requirement for Snf2l on progenitor homeostasis. The Ex6DEL GNPs showed delayed differentiation upon plating that was not attributed to changes in the Sonic Hedgehog pathway but was associated with overexpression of numerous positive effectors of proliferation, including targets of Wnt activation. Transcriptome analysis identified increased expression of Fosb and Fosl2 while ATACseq experiments identified a large increase in chromatin accessibility at promoters many enriched for Fos/Jun binding sites. Nonetheless, the elevated proliferation index was transient and the Ex6DEL cultures initiated differentiation with a high concordance in gene expression changes to the wild type cultures. Genes specific to Ex6DEL differentiation were associated with an increased activation of the ERK signaling pathway. Taken together, this data provides the first indication of how Smarca1 mutations alter progenitor cell homeostasis and contribute to changes in brain size.

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Section: Resultsmentioning

confidence: 99%

Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation

Goodwin

Zapata

Timpano

et al. 2021

Front. Mol. Neurosci.

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“…We first confirmed that WNT/CTNNB1 signaling is indeed hyperactivated in CHIR99021 treated organoids. To this end, we analyzed the response pattern of a curated set of 21 genes that have previously been reported to be activated by WNT/CTNNB1 signaling in the mammary gland or in other tissues (Boonekamp et al, 2021; Fafilek et al, 2013; Szemes et al, 2018; Wang et al, 2015; Yu et al, 2016). We made sure to include multiple bona-fide feedback targets, including Axin2 and Lgr5 (Supplementary File 2).…”

Section: Resultsmentioning

confidence: 99%

Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

Mourão

et al. 2021

Preprint

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In the past forty years, the WNT/CTNNB1 signaling pathway has emerged as a key player in mammary gland development and homeostasis. While also evidently involved in breast cancer, much unclarity continues to surround its precise role in mammary tumor formation and progression. This is largely due to the fact that the specific and direct effects of hyperactive WNT/CTNNB1 signaling on the mammary epithelium remain unknown. Here we use a primary mouse mammary organoid culture system to close this fundamental knowledge gap. We show that hyperactive WNT/CTNNB1 signaling induces competing cell proliferation and differentiation responses. While proliferation is dominant at lower levels of WNT/CTNNB1 signaling activity, higher levels cause reprogramming towards an epidermal cell fate. We show that this involves de novo activation of the epidermal differentiation cluster (EDC) locus and we identify master regulatory transcription factors that likely control the process. This is the first time that the molecular and cellular dose-response effects of WNT/CTNNB1 signaling in the mammary epithelium have been dissected in such detail. Our analyses reveal that the mammary epithelium is exquisitely sensitive to small changes in WNT/CTNNB1 signaling and offer a mechanistic explanation for the squamous differentiation that is observed in some WNT/CTNNB1 driven tumors.

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“…β-catenin then translocates to the nucleus, where it drives the expression of target genes of Transcription factor/Lymphoid enhancer-binding factor (TCF/LEF) family transcription factors. This gene expression signature, which includes numerous shared as well as tissue-specific gene targets [ 3 ], promotes stem cell maintenance, cell cycle progression, and cell proliferation, and is thus essential for organogenesis and tissue homeostasis. Besides Wnt/β-catenin signaling, there are several non-canonical Wnt pathways that branch off at the receptor level and at the level of the destruction complex [ 4 , 5 ].…”

Section: Wnt Signaling In Cancermentioning

confidence: 99%

“…Selective gene expression is then achieved by the differential action of the four TCF/LEF transcription factors, which have overlapping but non-identical functions and target genes [ 33 , 34 , 35 ]. However, it is unlikely that this mechanism alone explains the different Wnt transcriptional signatures that have been observed even in developmentally related tissues [ 3 ].…”

Section: Wnt Signaling In Cancermentioning

confidence: 99%

Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Koch

2021

Cancers

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Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

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Identification of novel human Wnt target genes using adult endodermal tissue-derived organoids

Cited by 29 publications

References 47 publications

Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation

Impaired SNF2L Chromatin Remodeling Prolongs Accessibility at Promoters Enriched for Fos/Jun Binding Sites and Delays Granule Neuron Differentiation

Hyperactive WNT/CTNNB1 signaling induces a competing cell proliferation and epidermal differentiation response in the mouse mammary epithelium

Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

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