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Multicilin drives centriole biogenesis via E2f proteins

ABSTRACT: Biochemistry suggests e2f4 forms a complex with the coiled-coiled protein multicilin (MCIDAS), a protein that is necessary and sufficient to specify multiciliated cells in vertebrates. Here, we performed RNAseq on Xenopus laevis ectoderm in the presence of multicilin alone or multicilin and a dominant-negative e2f4 construct. We also performed ChIPseq on e2f4 in the presence or absence of multicilin. Taken together, these data demonstrate how multicilin affects e2f4 genomic targets and their downstream transcription.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE59309 | GEO | 2014/07/10

SECONDARY ACCESSION(S): PRJNA255038

REPOSITORIES: GEO

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Multicilin drives centriole biogenesis via E2f proteins

Project description:Biochemistry suggests e2f4 forms a complex with the coiled-coiled protein multicilin (MCIDAS), a protein that is necessary and sufficient to specify multiciliated cells in vertebrates. Here, we performed RNAseq on Xenopus laevis ectoderm in the presence of multicilin alone or multicilin and a dominant-negative e2f4 construct. We also performed ChIPseq on e2f4 in the presence or absence of multicilin. Taken together, these data demonstrate how multicilin affects e2f4 genomic targets and their downstream transcription. RNAseq: misexpression of multicilin-HGR +/- dominant-negative e2f4 messenger RNAs in X. laevis animal caps, multicilin induced with dexamethasone at mid-stage 11 and harvested at 3 timepoints (3, 6, and 9 hours after induction, roughly corresponding to stages 13, 16, and 18) with 3 biological replicates. ChIPseq: misexpression of e2f4-GFP +/- multicilin-HGR messenger RNAs in X. laevis animal caps, multicilin induced at mid-stage 11 and harvested at one timepoint (6 hours after induction, roughly corresponding to stage 16), immunoprecipitated with anti-GFP and sequenced; 2 biological replicates. Background was input prior to IP.

2014-07-10 | E-GEOD-59309 | biostudies-arrayexpress

Histone modification and transcription factor ChIPseq of Xenopus laevis epithelial progenitors

Project description:To determine the positions of promoters and enhancers in developing Xenopus laevis epithelial progenitors, we performed ChIPseq on the histone modifications H3K4me3 and H3K27ac. We also performed ChIPseq on the transcription factors foxj1 (in the presence or absence of rfx2), myb (in the presence or absence of multicilin), and rad21. Some embryos were harvested as wild-types; in other experiments, we injected embryos with mRNAs encoding FLAG-foxj1 (with and without rfx2 morpholino) or GFP-myb (with and without an inducible form of multicilin (mcidas-HGR)). We then isolated epithelial progenitors surgically and, when injected with multicilin, induced at mid-stage 11. We then harvested chromatin at 9 hours after induction (roughly stage 18) and performed ChIPseq using antibodies against endogenous targets (H3K4me3, H3K27ac, rad21) or protein tags (FLAG, GFP). We then sequenced these libraries, aligned the reads to the X. laevis genome (version 9.1) with bwa mem and called peaks with HOMER, using input as background.

2016-02-23 | E-GEOD-78176 | biostudies-arrayexpress

3D chromosomal capture of X. laevis

Project description:To determine 3D chromosomal structure in differentating ectoderm of the frog Xenopus laevis, we performed tethered conformation capture (TCC) (PMID: 22198700) on wild-type dissected ectoderm and ectoderm injected with multicilin. We used these data to investigate possible differences between these conditions (we found very few) and also to determine the positions of topologically-associated domains (TADs). These data were also used to facilitate chromosome-level assembly of the X. laevis genome.

2015-12-29 | GSE76363 | GEO

GEMC1 and MCIDAS interactions with SWI/SNF complexes regulate the multiciliated cell-specific transcriptional program

Project description:Multiciliated cells (MCCs) project dozens to hundreds of motile cilia from their apical surface to promote the movement of fluids or gametes in the mammalian brain, airway or reproductive organs. Differentiation of MCCs requires the sequential action of the Geminin family transcriptional activators, GEMC1 and MCIDAS, that both interact with E2F4/5-DP1. How these factors activate transcription and the extent to which they play redundant functions remains poorly understood. Here, we carried out a transcriptomic analysis to compare the relative influence of GEMC1 and MCIDAS on gene expression.

2023-02-27 | GSE161197 | GEO

RNAseq profiling of multiciliated cells

Project description:To determine what genes are upregulated in multiciliated cells, we manipulated Xenopus laevis ectoderm to either make more or fewer of this cell type with multiple approaches across multiple timepoints. By finding differentially expressed genes in common across all comparisons in which multiciliated cell number changed, we obtained a robust, but conservative, core group of multiciliated cell genes.

2015-12-25 | GSE76342 | GEO

RBL2 represses the transcriptional activity of Multicilin to inhibit multiciliogenesis

Project description:A core pathophysiology underlying many respiratory diseases is multiciliated cell dysfunction leading to inadequate mucociliary clearance. Due to the prevalence and high variability of etiologies of MCC dysfunction in respiratory diseases, it is critical to understand the mechanisms controlling multiciliogenesis that may be targeted to restore functional mucociliary clearance. Multicilin, in complex with E2F4, is necessary and sufficient to drive multiciliogenesis in airway epithelium, however this does not apply to all cell types nor occur evenly across all cells in the same cell population. In this study we investigated we further investigate how co-factors regulate the ability of Multicilin to drive multiciliogenesis. Combining data in mouse embryonic fibroblasts and human bronchial epithelial cells we identify RBL2 as an inhibitor of the transcriptional activity of Multicilin. Both knockdown of RBL2 and phosphorylation of RBL2 driven by exposure to an air-liquid interface in the presence of Multicilin activated multiciliogenesis demonstrating a dynamic interaction regulating the differentiation of human airway epithelial cells. Identification of this mechanism has important implications for facilitating MCC differentiation in diseases where mucociliary clearance is impeded.

2024-01-31 | GSE235682 | GEO

Mucociliary epidermis RNA-seq data from controls and after manipulation of cell fates by Notch (suh-dbm, nicd) and cell type controlers (Foxa1MO, dnMCIDAS)

Project description:This study was conducted to investigate the effects of enriching or depleting cell types in mucociliary organoids in Xenopus laevis. (1) Uninjected control embryos were compared to (2) inhibition of Notch signaling (suh-dbm) which enriches ionocytes and multiciliated cells, (3) inhibition of Notch and suppression of MCIDAS (suh-dbm + dnMCIDAS) which enriches ionocytes and depletes multiciliated cells, (4) overactivation of Notch (nicd) which suppresses ionocytes and multiciliated cells and promotes small secretory cells and basal cells, (5) knockdown of foxa1 (foxa1MO) which depletes small secretory cells. Embryos were injected at 2-4 cell stage and were used to generate animal cap explants at embryonic stage 8. Explants were grown into mucociliary organoids and collected at embryonic stages 10.5, 16, 25, and 32 for total RNA extraction.

2022-10-18 | GSE215373 | GEO

Histone modification and transcription factor ChIPseq of Xenopus laevis epithelial progenitors

2016-02-23 | GSE78176 | GEO

DNA damage-p53/p21 response contributes to ependymal cell development

Project description:Multiciliated Ependymal Cells and Adult Neural Stem Cells are components of the adult neurogenic niche, essential for brain homeostasis. These cells share a common glial cell lineage regulated by the Geminin family members Geminin and GemC1/Mcidas. Ependymal precursors require GemC1/Mcidas expression to massively amplify centrioles and become multiciliated cells. Here we show that GemC1-dependent differentiation occurs mostly in cycling Radial Glial Cells, in which a DNA damage response, including replicative stress and dysfunctional telomeres, arrests the cell cycle after the G1/S restriction point due to the activation of the p53-p21 pathway, which contributes to centriole amplification. Telomerase expression in Radial Glial Cells impairs ependymal differentiation and favors the Neural Stem Cell fate.

2021-09-21 | GSE184397 | GEO

Analysis of initial step of multiciliogenesis during the differentiation of adult airway progenitors

Project description:Multiciliated cells are crucial for fluid and ion transport in epithelia of a variety of organs and their impaired development and function are seen in human diseases affecting the brain, respiratory, and reproductive tracts. Multiciliogenesis requires activation of a specialized transcription program coupled to complex cytoplasmic events that lead to large-scale centriole amplification to generate multicilia. Yet, it remains unclear how these events are coordinated to initiate multiciliogenesis in epithelial progenitors. Here we identify an unsuspected mechanism orchestrated by the transcription factor E2f4 essential to integrate these processes. We show that after inducing a transcriptional program of centriole biogenesis, E2f4 translocates to the cytoplasm to become a core component of structures classically identified as fibrous granules (FG), acting as organizing centers for deuterosome assembly and centriole amplification. Remarkably, loss of cytoplasmic E2f4 prevents FG aggregation, deuterosome assembly and multicilia formation even when E2f4’s transcriptional function is preserved. Moreover, in E2f4-deficient cells multiciliogenesis is rescued only if both nuclear and cytoplasmic E2f4 activities are restored. Thus, E2f4 integrates previously unrelated nuclear and cytoplasmic events of the multiciliated cell program.

2017-08-30 | GSE73331 | GEO

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