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High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency

ABSTRACT: Using a high throughput splicing reporter assay, we tested 1,080 single nucleotide variants in POU1F1, a key transcription factor essential for pituitary development. Our saturation splicing effect map identifies 96 splice disruptive variants, including 14 synonymous variants, of which 8 were found in unrelated patients diagnosed with hypopituitarism.

ORGANISM(S): Chlorocebus aethiops Homo sapiens

PROVIDER: GSE172504 | GEO | 2021/04/22

REPOSITORIES: GEO

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High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency

Project description:High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency

| PRJNA723581 | ENA

High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency.

Project description:Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.

| S-EPMC8387473 | biostudies-literature

DNA methylation analysis in MCF-7 cell line with overexpression of POU1F1

Project description:The transcription factor POU1F1 plays an important role in breast cancer. It has been described that POU1F1 is capable of regulating the expression of different genes involved in cell proliferation, apoptosis and cell plasticity. The mechanism by which POU1F1 carries out these regulations is still unknown, and epigenetics is one of the possible causes. Epigenetics refers to modifications in gene expression that are heritable through cell division and that occur without changes in the DNA sequence. DNA methylation is one of the most important epigenetic mechanisms.

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Project description:POU1F1 regulates, in the pituitary, the development of the prolactin-, growth hormone- and thyrotropin ß-expressing lineages and the expression of these hormone in the mature pituitary through the direct regulation of their promoters. Besides these functions, POU1F1 is also involved in other cellular processes in the pituitary, such as cell division and survival, but the genomic targets involved in these actions are not known. The present ChIP-chip study identified a large number of hitherto unknown potential direct targets that might be involved in these actions, such as Tcf4, Lmo4, Pax6, Trp53 etc. ChIP-chip was done from pregnant female mouse (C57Bl/6J) pituitary (3 pools of 12 pituitary anterior lobes, corresponding to three biological replicates) with POU1F1 (PIT-1)

2011-10-28 | E-GEOD-33318 | biostudies-arrayexpress

Control of the anterior pituitary cell lineage regulator POU1F1 by the stem cell determinant Musashi

Project description:The high energetic cost of reproduction requires that female fertility be closely linked to metabolic status. However, the mechanisms by which the metabolic and reproductive systems communicate is still largely undefined. We have previously reported that signaling through the major metabolic cytokine leptin controls levels of the pituitary maturation determinant POU1F1 (also referred to as Pit1) that is required for optimal reproductive function. These studies further indicated that leptin increases POU1F1levels in females by promoting Pou1f1 mRNA translation, although the mechanism ofPou1f1 mRNA translation control is unknown. In this study, we report that the stem cell marker and mRNA translational control protein, Musashi, represses translation of the Pou1f1 mRNA. In FACS-sorted purified female somatotropes, Msi1 mRNA and Musashi protein levels are increased in the mouse model that lacks leptin signaling (Gh-CRE leprLepr-null), coincident with the observed attenuation of Pou1f1 mRNA translation. Single-cell RNA sequencing of pituitary cells from control female animals indicates that Msi1 and Pou1f1 mRNAs are co-expressed in Gh-expressing cells and immunocytochemistry analyses of these cells confirms that Musashi protein is present in the GH-containing somatotrope population. We demonstrate that Musashi interacts directly with the Pou1f1 mRNA 3’ UTR and exerts translational repression of a Pou1f1 mRNA translation reporter in vitro, and interacts with the Pou1f1 mRNA in vivo. These findings indicate a critical role for Musashi-mediated mRNA translational regulation in the coordination between metabolic status and the maturation of pituitary somatotropes that is required for optimized reproductive function .

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Reprogramming breast cancer cells to breast cancer stem cells-like by the POU1F1 transcription factor

Project description:POU1F1 (also named PIT-1) is a well-known transcription factor involved in embryonic and adult pituitary development that has also been analyzed for its role in breast cancer . This study provides compelling evidence of POU1F1 in reprogramming breast cancer cells into BCSC-like. Our data demonstrates that POU1F1 induces a BCSC-like phenotype in breast tumor cells by deregulating markers such as CD24, CD44, CD133, and ALDH. These phenotypic modifications are correlated with functional changes, i.e. higher clonogenicity, increased mammospheres formation, and increased glycolysis metabolism. In addition, using in vivo immunodeficient mice models we found that a subpopulation of ALDHhigh cells from the POU1F1 overexpressing MCF-7 cells possess high tumor-initiating capacity, high resistance to chemo- and radiotherapy, and reduced overall survival. Mechanistically, POU1F1 induces an increase in IL-6 mRNA expression and raises IL-6 in the culture medium. This activates the IL-6/JAK/STAT3 pathway, which in turn increases ALDH mRNA expression.

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Modification of genes expression in the somatolactotrope GH4C1 cell line in presence of the dominant negative mutant POU1F1(R271W)

Project description:The anterior pituitary-specific transcription factor POU1F1 (also called PIT-1) was initially identified and cloned as a transactivator of PRL, GH and TSHß subunit genes. Different studies indicated that POU1F1 could also have other functions in these cells. The identification of new targets of this factor could be useful to obtain a better understanding of these functions. Gene expression microarray assays were used to detect genes that have their expression modified in somatolactotrope GH4C1 cells by the expression of a dominant negative form of POU1F1, POU1F1(R271W). Lentiviral vectors containing the transgene of interest under the control of the PGK promoter (pGK-POU1F1(R271W)-IRES-EGFP, or pGK-EGFP used as controls) were generated. After lentiviral transfer in GH4C1 cells were grown in regular medium for 4 days then cells were harvested and total RNA was purified.

2012-01-04 | E-GEOD-33311 | biostudies-arrayexpress

Modification of genes expression in the somatolactotrope GH4C1 cell line in presence of the dominant negative mutant POU1F1(R271W)

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ChIP-chip from pregnant female mouse pituitary with POU1F1 (PIT-1)

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Project description:The failure of treatment to deal with intractable cancer cells has raised the question of whether there is a special population of cells in tumor heterogeneity that exhibit resistant phenotypes that favor micrometastasis and have the potential to cause recurrence. One of the current points of view is that most solid cancers, including breast cancer, are stem cell diseases, and that these CSCs are critical to dissemination and metastasis. Our objective is to study the role of POU1F1 in breast cancer cell plasticity. Specifically, we will evaluate whether POU1F1 could modify the phenotype of normal -epithelial- cells to induce its transformation into CSCs/BCSCs

2025-05-06 | GSE287732 | GEO

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