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The SON splicing factor is required for intracellular trafficking that promotes centriole assembly

ABSTRACT: Control of the number of centrosomes is critical for cell division, trafficking and cilia. Regulation of centrosome number occurs through the precise duplication of centrioles that reside in the center of centrosomes. Here we explored transcriptional control of centriole assembly by focusing on alternative splicing factors in isolation from other cell cycle processes. Of five splicing factors originally identified as required for centriole assembly, only SON is specifically required. Procentriole assembly is severely disrupted when SON is reduced but early centriole assembly events still occur. Whole genome mRNA sequencing identified thousands of genes whose splicing and expression are affected by the reduction of SON, with an enrichment of genes involved in the microtubule cytoskeleton. SON is required for the proper splicing and expression of the centriolar satellite protein, CEP131. Fluorescence microscopy and electron tomography establish key differences to the trafficking and microtubule network around the centrosomes that contribute to the centriole assembly defects. This establishes SON as required for centriole assembly, partially through its activity in splicing CEP131 and through control of microtubules organized by the centrosome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164278 | GEO | 2021/12/22

REPOSITORIES: GEO

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The SON splicing factor is required for intracellular trafficking that promotes centriole assembly

Project description:The SON splicing factor is required for intracellular trafficking that promotes centriole assembly

| PRJNA689788 | ENA

Oncogene-like induction of cellular invasion from centrosome amplification

Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation. genome-wide human SNP 6.0 arrays from Affymetrix was used to determine the copy number changes of MCF10A cells with extra centrosomes or depleted of MCAK after grown 4 days in 3-D cultures

2014-03-01 | E-GEOD-55042 | biostudies-arrayexpress

SON and its alternatively spliced isoforms control MLL complex-mediated H3K4me3 and transcription of leukemia-associated genes (ChIP-seq data)

Project description:Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy, but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia.

2016-03-24 | GSE76910 | GEO

Son Maintains Accurate Splicing of Pre-mRNAs Encoding Chromatin Modifiers

Project description:Exon and expression analysis of HeLa cells after knockdown of SON Serine-arginine-rich (SR) proteins play a key role in alternative pre-mRNA splicing in eukaryotes. Our laboratory recently showed that a large SR protein called Son has unique repeat motifs that are essential for maintaining the subnuclear organization of pre-mRNA processing factors in nuclear speckles. Motif analysis of Son highlights putative RNA interaction domains that suggest a direct role for Son in pre-mRNA splicing. A genome-wide screen was performed to identify putative human transcription and splicing targets of Son.

2011-12-22 | GSE28672 | GEO

Son Maintains Accurate Splicing of Pre-mRNAs Encoding Chromatin Modifiers

2011-12-22 | E-GEOD-28672 | biostudies-arrayexpress

Oncogene-like induction of cellular invasion from centrosome amplification

2014-03-01 | GSE55042 | GEO

Gene expression in mitotic tissues of Drosophila larvae without centrosomes or too many centrosomes

2012-08-20 | GSE35240 | GEO

RNA-Seq after knockdown of SON in human embryonic stem cells

Project description:Human embryonic stem cells (hESCs) harbor the ability to undergo lineage-specific differentiation into clinically relevant cell types. Transcription factors and epigenetic modifiers are known to play important roles in the maintenance of pluripotency of hESCs. However, little is known about regulation of pluripotency through splicing. In this study, we identify the spliceosome-associated factor SON as a novel factor essential for the maintenance of hESCs. Depletion of SON in hESCs results in the loss of pluripotency and cell death. Using genome-wide RNA profiling, we identified transcripts that are regulated by SON. Importantly, we confirmed that SON regulates the proper splicing of transcripts encoding for pluripotency regulators such as PRDM14, OCT4, E4F1 and MED24. Furthermore, we show that SON is bound to these transcripts in vivo. In summary, we connect a splicing-regulatory network for accurate transcription production to the maintenance of pluripotency and self-renewal of hESCs.

2013-08-29 | E-MTAB-1687 | biostudies-arrayexpress

Gene expression in mitotic tissues of Drosophila larvae without centrosomes or too many centrosomes

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2012-08-20 | E-GEOD-35240 | biostudies-arrayexpress

Sub-centrosomal mapping identifies augmin-TuRC as part of a centriole-stabilizing scaffold

Project description:Centriole biogenesis and maintenance are crucial for cells to generate cilia and assemble centrosomes that function as microtubule organizing centers (MTOCs). Centriole biogenesis and MTOC function both require the microtubule nucleator -tubulin ring complex (TuRC). It is widely accepted that TuRC nucleates microtubules from the pericentriolar material (PCM) that is associated with the proximal part of centrioles. However, TuRC also localizes more distally and in the centriole lumen, but the significance of these findings is unclear. Here we identify spatially and functionally distinct sub-populations of centrosomal TuRC. Luminal localization is mediated by augmin, which is linked to the centriole inner scaffold through POC5. Disruption of luminal localization impairs centriole integrity and interferes with cilium assembly. Defective ciliogenesis is also observed in TuRC mutant fibroblasts from a patient suffering from microcephaly with chorioretinopathy. These results identify a novel, non-canonical role of augmin-γTuRC in the centriole lumen that is linked to human disease.

2022-02-17 | PXD027352 | Pride

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