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RNAseq analysis of Xenopus laevis wildtype and emi2 mutant multiciliated cells during and post differentiation

ABSTRACT: Multiciliated cells (MCCs) form when progenitors massively expand centriole number, yielding the hundreds of basal bodies required to extend multiple motile cilia. This organelle biogenesis is promoted transcriptionally by Multicilin acting in a complex with the E2F transcription factors, which activates the expression of genes known to be involved required to form centrioles during the cell cycle, but also requires a cell cycle state required for the centrosome cycle. Multicilin also activates the expression of Emi2 (fbxo43) an inhibitor of the APC/C ubiquitin ligase. In Emi2 mutants, basal body formation during MCCl differentiation is blocked. RNAseq analysis is used to show that gene expression associated with MCC differentiation is upregulated normally in Emi2 mutants, but surprisingly is not downregulated when MCC differentiation is complete. Emi2 is required to promote the centrosomal cycle during MCC differentiation, but then also acts to turn off gene expression associated with centriole biogenesis in differentiated cells.

ORGANISM(S): Xenopus laevis

PROVIDER: GSE195635 | GEO | 2024/03/20

REPOSITORIES: GEO

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Project description:Multicilin drives centriole biogenesis via E2f proteins

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Identification of CDC20/CDC20B partners in HEK cells demonstrates that CDC20, but not CDC20B, interacts with multiple APC/C components

Project description:Multiciliated cells (MCCs) harbour dozens to hundreds of motile cilia, which beat in a synchronized and directional manner, thus generating hydrodynamic forces important in animal physiology. In vertebrates, MCC differentiation critically depends on the synthesis and release of numerous centrioles by specialized structures called deuterosomes. Little is known about the composition, organization and regulation of deuterosomes. Here, single-cell RNA sequencing reveals that human deuterosome-stage MCCs are characterized by the expression of many cell cycle-related genes. We further investigated the uncharacterized vertebrate specific cell division cycle 20B (CDC20B) gene, the host gene of microRNA-449abc. We show that the CDC20B protein associates to deuterosomes and is required for the release of centrioles and the subsequent production of cilia in mouse and Xenopus MCCs. CDC20B interacts with PLK1, which has been shown to coordinate centriole disengagement with the protease Separase in mitotic cells. Strikingly, over-expression of Separase rescued centriole disengagement and cilia production in CDC20B-deficient MCCs. This work reveals the shaping of a new biological function, deuterosome-mediated centriole production in vertebrate MCCs, by adaptation of canonical and recently evolved cell cycle-related molecules. A specific aim of this mass spectrometry experiment was to verify on immunoprecipitated protein complexes from CDC20 or CDC20B transfected HEK cells that CDC20, but not CDC20B, interacts with multiple APC/C components.

2019-04-03 | PXD010629 | Pride

Edf1 control multiciliated ependymel cell associated genes expression

Project description:The development and differentiation of Multiciliated ependymal cells are crucial for brain development, with defects leading to conditions such as congenital hydrocephalus. The differentiation of MCCs depends on a unique transcriptional program. Our study shows that Edf1, previously implicated as a transcriptional co-factor, is consistently expressed during MCC development and positively regulates key genes involved in multiciliogenesis and physiological functions.

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LSD1 inhibition induces differentiation and cell death in Merkel cell carcinoma

Project description:Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for proliferation and maintaining cell identity in MCC. There is growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.

2020-11-03 | PXD020590 | Pride

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