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Bulk ATAC-seq of Foxe1KO and control Nkx2-1/mKO2+ mouse ESC-derived cells

ABSTRACT: Functional thyroid follicles generation in vitro is obtained at high efficiency by doxycycline-mediated expression of Nkx2-1 and Pax8, two proteins involved in early specification of thyroid lineage. Although those factors are sufficient to induce thyroid specification in vitro, other players, such as Foxe1, are also present in early thyroid primordium and its loss-of-function is responsible for thyroid congenital defects in mice and humans. Here we show that Foxe1KO mESCs can be induced to differentiate towards thyroid lineage but the efficiency of thyroid follicular cells generated is drastically low. Moreover, correct expression of maturation genes and capacity to produce thyroid hormone in vitro are completely disrupted. On the other hand, Nkx2-1 expressing cells derived from Foxe1KO have an unexpected ability to deviate to a lung epithelium differentiation program and form organoids containing multiple lung cell types. These findings demonstrate that Foxe1 is required to reinforce thyroid cell fate in vitro and to promote terminal maturation of thyroid follicles.

ORGANISM(S): Mus musculus

PROVIDER: GSE182676 | GEO | 2023/12/31

REPOSITORIES: GEO

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Bulk RNA-Seq of Foxe1KO and control Nkx2-1/mKO2+ mouse ESC-derived cells

Project description:Functional thyroid follicles generation in vitro is obtained at high efficiency by doxycycline-mediated expression of Nkx2-1 and Pax8, two proteins involved in early specification of thyroid lineage. Although those factors are sufficient to induce thyroid specification in vitro, other players, such as Foxe1, are also present in early thyroid primordium and its loss-of-function is responsible for thyroid congenital defects in mice and humans. Here we show that Foxe1KO mESCs can be induced to differentiate towards thyroid lineage but the efficiency of thyroid follicular cells generated is drastically low. Moreover, correct expression of maturation genes and capacity to produce thyroid hormone in vitro are completely disrupted. On the other hand, Nkx2-1 expressing cells derived from Foxe1KO have an unexpected ability to deviate to a lung epithelium differentiation program and form organoids containing multiple lung cell types. These findings demonstrate that Foxe1 is required to reinforce thyroid cell fate in vitro and to promote terminal maturation of thyroid follicles.

2023-12-31 | GSE182480 | GEO

Single-cell RNA-Seq of Foxe1KO mouse ESC-derived cells

2023-12-31 | GSE182337 | GEO

Glis3 regulates the expression of thyroid hormone synthetic genes in coordination with other thyroid transcription factors

Project description:Comparison of cistromes from PAX8, NKX2.1, and FOXE1 ChIP-Seq analysis using mouse thyroid gland and rat thyrocyte PCCl3 cells revealed that there is a significant overlap between GLIS3 binding regions and those of PAX8, NKX2.1, and FOXE1 in genes associated with thyroid hormone biosynthesis.

2023-04-06 | GSE207777 | GEO

Thyroid progenitors are robustly derived from embryonic stem cells through transient, developmental stage-specific overexpression of Nkx2-1

Project description:The clinical importance of anterior foregut endoderm (AFE) derivatives, such as thyrocytes, has led to intense research efforts for their derivation through directed differentiation of pluripotent stem cells (PSCs). Here we identify transient overexpression of the transcription factor (TF) NKX2-1 as a powerful inductive signal for the robust derivation of thyrocyte-like cells from mouse PSC-derived AFE. This effect is highly developmental stage-specific and dependent upon FOXA2 expression levels and precise modulation of BMP and FGF signaling. The majority of the resulting cells express thyroid TFs (Nkx2-1, Pax8, Foxe1, Hhex) and thyroid hormone synthesis-related genes (Tg, Tpo, Nis, Iyd) at levels similar to adult mouse thyroid and give rise to functional follicle-like epithelial structures in Matrigel culture. Our findings demonstrate that NKX2-1 overexpression converts AFE to thyroid epithelium in a developmental time-sensitive manner and suggest a general methodology for manipulation of cell fate decisions of developmental intermediates.

2016-12-20 | GSE92572 | GEO

Whole transcriptome sequencing of the human thyroid primary cells with knock-down of the FOXE1 gene

Project description:FOXE1 gene (also known as thyroid transcription factor 2) has been reported to be essential for thyroid gland development and the maintenance of thyroid differentiated status. Current knowledge of FOXE1 regulated genes is mostly based on the expression and functional studies using cell line models. Here we report gene expression profiles of human thyroid primary cells on Day 5 treated with FOXE1 siRNA or nontarget siRNA. The primary cells were generated from fresh nontumorous thyroid tissues obtained from thyroid cancer patients. A number of new dysregulated genes of FOXE1 were discovered, including THBS1 and IGFBP3, which have not been reported as FOXE1 regulated genes before. This study reveals a novel role of FOXE1 in downstream gene regulation and provides a new explanation of FOXE1’s function in thyroid cancer.

2017-02-24 | GSE83919 | GEO

RNA-Seq of human epithelial follicular cell line Nthy-ori 3-1 treated for 24 hours with benzo[a]pyrene or DMSO solvent control and mouse embryonic stem cell-derived thyroid follicles treated for 24 hours with DMSO solvent control.

Project description:The human epithelial follicular cell line Nthy-ori 3-1 was treated with 10 uM or 1 uM benzo[a]pyrene in 0.5% DMSO or with 0.5% DMSO only for 24 hours. Thyroid follicles were differentiated from a recombinant mESC line (A2LoxNkx2-1-Pax8) and treated with 0.5% DMSO for 24 hours. For Nthy-ori 3-1 samples, total RNA was extracted and used to prepare combined mRNA/miRNA libraries, poly(A) libraries and small RNA libraries. For thyroid follicles samples, total RNA was extracted and used to prepare combined mRNA/miRNA libraries.

2022-12-14 | E-MTAB-12078 | biostudies-arrayexpress

Transcriptional profiles of induced thyroid follicular like cells.

Project description:Defined transcription factors can direct changes in programmed cell fate to give rise to various cell lineages, in contrast to the one-way street during development. Direct lineage conversions from fibroblasts occur in all the three germ layer derivatives- neurons, cardiomyocytes, and hepatocytes. However, direct reprogramming of thyroid lineages has not been accomplished yet. Previous studies demonstrated that exogenous Pax8 and Nkx2.1, which are indispensable for proper thyroid development, enable the pluripotent stem cell-derived definitive endoderm to differentiate into functional thyroid follicular cells. This raised the question whether a cocktail of thyroid development-related transcription factors can directly convert fibroblasts into thyroid follicular cells in vitro. In the current study, we found that induction of defined transcription factors is able to generate thyroid follicular cells from fibroblasts. Further, Pax8, Nkx2.1, Foxe1, Oct3/4, Sox2, Klf4, and c-Myc were sufficient to generate thyroglobulin (Tg)+/EpCAM+ colonies from mouse embryonic fibroblasts, and these colonies built three-dimensional (3D) follicular-like structures in matrigel-based 3D culture. These induced thyroid follicular-like cells, named iTF cells, were morphologically and transcriptionally similar to those of the adult thyroid. Finally, iTF cells were transplantable into the kidney capsule, and formed huge follicular structures in vivo as well. Our study therefore reveals that thyroid lineage can be directly derived from fibroblasts in a single step, and contributes to rapid translational research on human thyroid diseases such as hyperthyroidism.

2016-09-30 | GSE76266 | GEO

Single-cell RNA-Seq of mouse thyroid organoid

Project description:The thyroid gland regulates metabolism and growth via secretion of thyroid hormone by thyroid follicular cells (TFCs). Loss of TFCs, by cellular dysfunction, autoimmune destruction or surgical resection, underlies hypothyroidism. Recovery of thyroid hormone levels by transplantation of mature TFCs derived from stem cells in vitro holds great therapeutic promise. However, the utilization of in vitro derived tissue for regenerative medicine is restricted by the efficiency of differentiation protocols to generate mature organoids. Here, to improve the differentiation efficiency for thyroid organoids, we utilized single-cell RNA-Seq to chart the molecular steps undertaken by individual cells during the in vitro transformation of mouse embryonic stem cells to TFCs. Our single-cell atlas of mouse organoid systematically and comprehensively identifies, for the first time, the cell-types generated during production of thyroid organoids. Using pseudotime analysis, we identify molecular pathways that regulate thyroid maturation in vitro. Our study highlights the potential of single-cell molecular characterization in understanding and improving thyroid maturation, and paves the way for identification of therapeutic targets against thyroid disorders.

2021-05-26 | GSE163818 | GEO

RNA-Seq of in vitro thyroid mouse organoids exposed to a dose range of phthalates for 24 hours. ATAC-Seq of human epithelial thryoid cell line Nthy-ori 3-1 exposed to DEHP or DINP (1 uM) for 5 days

Project description:Mouse RNA-Seq: cells derived from recombinant embryonic stem cell line (A2LoxNkx2-1-Pax8) were used. Mouse embryonic stem cell-derived thyroid follicles were exposed to a dose range of phthalates (DEHP, DIDP, DINP at 1-10-100 nM-1-10 uM; DnOP at 2-20-200 nM-2-20 uM) for 24 hours. Every condition was performed in triplicate. Untreated (n = 2) and 0.5% DMSO solvent (n = 5) controls were included. Combined mRNA/miRNA libraries were prepared and RNA-Seq performed. Human ATAC-seq: the human epithelial thyroid cell line, Nthy-ori 3-1, was exposed to DEHP or DINP for 5 days (n = 6), and ATAC-Seq was performed. 0.5% DMSO control samples (n = 6) were included.

2023-09-03 | E-MTAB-12830 | biostudies-arrayexpress

Gene expression profile changes upon knock-down of Pax8

Project description:In order to define the transcriptional network functionally regulated by Pax8 as well as infer its direct targets, we performed RNAi to knock-down Pax8 gene in FRTL-5 thyroid cells. Expression data from three independent silencing experiments were analyzed by microarray technology unraveling 2815 genes differentially expressed between silenced cells and controls. Of these, 1421 genes were down-regulated and 1394 genes were up-regulated 72hrs after Pax8 silencing. The results obtained suggest that Pax8 regulates numerous pathways, some of which involved in the regulation of cell cycle, thyroid cancer and apoptosis, thus confirming that Pax8 is a master regulatory gene. Rat differentiated thyroid cells from FRTL-5 line were transfected with siGENOME Pax8 siRNA (siPax8, experimental) or siGENOME Non-Targeting siRNA (ntPax8, controls). The trascriptome from three siPax8 biological replicates, 72 hours after transfection, was compared to the trascriptome from 3 control ntPax8 biological replicates. Microarray analysis was performed at gene-level using the AffymetrixGeneChip Rat Gene 1.0 ST array

2011-12-20 | E-GEOD-29341 | biostudies-arrayexpress

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