Role of estrogen receptor beta in neural differentiation of mouse embryonic stem cells

Varshney, Mukesh; Inzunza, José; Lupu, Diana; Ganapathy, Vaidheeswaran; Antonson, Per; Rüegg, Joëlle; Nalvarte, Ivan; Gustafsson, Jan Åke

doi:10.1073/pnas.1714094114

Cited by 38 publications

(51 citation statements)

References 56 publications

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“…The total RNA was used to prepare biotinylated cDNA according to the GeneChip WT Plus Reagent Kit labeling protocol (P/N 902281). Fragmented cDNA was hybridized to mouse Clariom D (MTA 1.0, covering >214,000 coding and noncoding transcripts variants) arrays (Affymetrix) and analysis was performed as described earlier (44). Genes were filtered for a minimum log 2 change of 1.5 or greater across the samples.…”

Section: Methodsmentioning

confidence: 99%

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Warner

Montanholi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Disagreements about the phenotype of estrogen receptor β (ERβ) knockout mouse, created by removing the DNA-binding domain of the ERβ gene or interruption of the gene with a neocassette (Oliver Smithies ERβ knockout mice [ERβOS−/−]), prompted us to create an ERβ knockout mouse by deleting the ERβ gene with the use of CRISPR/Cas9 technology. We confirmed that the ERβ gene was eliminated from the mouse genome and that no ERβ mRNA or protein was detectable in tissues of this mouse. Overall the phenotype of the ventral prostate (VP) and mammary gland (MG) in ERβcrispr−/−mice was similar to, but more severe than, that in the ERβOS−/−mice. In the VP of 6-mo-old ERβcrispr−/−mice there was epithelial hyperplasia, fibroplasia, inflammation, stromal overgrowth, and intraductal cancer-like lesions. This was accompanied by an increase in Ki67 and P63 and loss in DACH1 and PURα, two androgen receptor (AR) repressors. In the MG there was overexpression of estrogen receptor α and progesterone receptor, loss of collagen, increase in proliferation and expression of metalloproteases, and invasive epithelium. Surprisingly, by 18 mo of age, the number of hyperplastic foci was reduced, the ducts of the VP and MG became atrophic, and, in the VP, there was massive immune infiltration and massive desquamation of the luminal epithelial cells. These changes were coincident with reduced levels of androgens in males and estrogens in females. We conclude that ERβ is a tumor suppressor gene in the VP and MG where its loss increases the activity AR and ERα, respectively.

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Section: Methodsmentioning

confidence: 99%

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Warner

Montanholi

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…We assessed the lineage propensity of neuroepithelial cells derived from single-gene heterozygous ESCs (Twist1 +/-, Chd7 +/-, Chd8 +/and Whsc1 +/-) and compound heterozygous ESCs (Twist1 +/-;Chd7 +/-, Twist1 +/-;Chd8 +/and Twist1 +/-;Whsc1 +/-). ESCs were cultured in neurogenic differentiation media, followed by selection and expansion of NECs ( Figure 7A) (Bajpai et al, 2010;Varshney et al, 2017). Samples were collected at day 0 (Bajpai et al, 2010;Varshney et al, 2017).…”

Section: Twist1 and Chromatin Regulators For Cell Fate Choice In Neurmentioning

confidence: 99%

“…ESCs were cultured in neurogenic differentiation media, followed by selection and expansion of NECs ( Figure 7A) (Bajpai et al, 2010;Varshney et al, 2017). Samples were collected at day 0 (Bajpai et al, 2010;Varshney et al, 2017). B. i.…”

Section: Twist1 and Chromatin Regulators For Cell Fate Choice In Neurmentioning

confidence: 99%

TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation

Fan

Masamsetti

Sun

et al. 2020

Preprint

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Protein interaction is critical molecular regulatory activity underlining cellular functions and precise cell fate choices. Using TWIST1 BioID-proximity-labelling and network propagation analyses, we discovered and characterized a TWIST-chromatin regulatory module (TWIST1-CRM) in the neural crest cell (NCC). Combinatorial perturbation of core members of TWIST1-CRM: TWIST1, CHD7, CHD8, and WHSC1 in cell models and mouse embryos revealed that loss of the function of the regulatory module resulted in abnormal specification of NCCs and compromised craniofacial tissue patterning. Our results showed that in the course of cranial neural crest differentiation, phasic activity of TWIST1 and the interacting chromatin regulators promote the choice of NCC fate while suppressing neural stem cell fates, and subsequently enhance ectomesenchyme potential and cell motility. We have revealed the connections between TWIST1 and potential neurocristopathy factors which are functionally interdependent in NCC specification. Moreover, the NCC module participate in the genetic circuit delineating dorsal-ventral patterning of neural progenitors in the neuroepithelium.

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“…Co-localization of H3K27ac as well as Nanog, Sox2 and Oct4 with upregulated YAP peaks further increased the expression significantly ( Supplementary Figure S4B ). Of note, the genes with increased YAP binding and upregulated expression in Mst KO ESCs include ectoderm and neural differentiation related genes such as Msln ( 50 ), Htra1 ( 51 , 52 ), Mycn ( 53 ) and Cdh4 ( 54 ). On the other side, Zfp42 , a gene with reduced YAP binding in Mst KO ESCs showed significantly lower expression in the Mst KO ESCs than WT ESCs (Figure 3C ).…”

Section: Resultsmentioning

confidence: 99%

“…As anticipated, a subset of genes regulated by TEs in WT ESCs were converted to be regulated by SEs with increased gene expression in Mst KO ESCs (Figure 4G , Supplementary Figure S6D ). These genes included Msln ( 50 ), Mdga1 ( 57 ), Htra1 ( 51 ) and Tesc ( 58 ), which mark neuroectoderm differentiation; Nono ( 59 ), Ajuba ( 60 ) and Vegfa ( 61 ), which inhibit mesendoderm or downstream lineage differentiation; and YAP negative regulator Frmd6 ( 62 ) (Figure 4G ). Mst KO induced significant increase of YAP enrichment on these genes.…”

Section: Resultsmentioning

confidence: 99%

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers

Sun

Ren

Cun

et al. 2020

Nucleic Acids Research

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Hippo-YAP signaling pathway functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. We found that knockout (KO) of Mst1 and Mst2, two key components of the Hippo signaling in mouse embryonic stem cells (ESCs), resulted in a disruption of differentiation into mesendoderm lineage. To further uncover the underlying regulatory mechanisms, we performed a series of ChIP-seq experiments with antibodies against YAP, ESC master transcription factors and some characterized histone modification markers as well as RNA-seq assays using wild type and Mst KO samples at ES and day 4 embryoid body stage respectively. We demonstrate that YAP is preferentially co-localized with super-enhancer (SE) markers such as Nanog, Sox2, Oct4 and H3K27ac in ESCs. The hyper-activation of nuclear YAP in Mst KO ESCs facilitates the binding of Nanog, Sox2 and Oct4 as well as H3K27ac modification at the loci where YAP binds. Moreover, Mst depletion results in novel SE formation and enhanced liquid-liquid phase-separated Med1 condensates on lineage associated genes, leading to the upregulation of these genes and the distortion of ESC differentiation. Our study reveals a novel mechanism on how Hippo-YAP signaling pathway dictates ESC lineage differentiation.

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Role of estrogen receptor beta in neural differentiation of mouse embryonic stem cells

Cited by 38 publications

References 56 publications

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene

TWIST1 and chromatin regulatory proteins interact to guide neural crest cell differentiation

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers

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