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Alternative promoters and splicing create multiple functionally distinct isoforms of estrogen receptor alpha in breast cancer and healthy tissues

ABSTRACT: Alternative promoters and splicing create multiple functionally distinct isoforms of estrogen receptor alpha in breast cancer and healthy tissues

PROVIDER: PRJNA858826 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20210200_1.fastq.gz	Fastqsanger.gz
	SRR20210201_1.fastq.gz	Fastqsanger.gz
	SRR20210202_1.fastq.gz	Fastqsanger.gz
	SRR20210203_1.fastq.gz	Fastqsanger.gz
	SRR20210204_1.fastq.gz	Fastqsanger.gz

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Alternative promoters and splicing create multiple functionally distinct isoforms of estrogen receptor alpha in breast cancer and healthy tissues

Project description:Estrogen receptor alpha (ER) is involved in cell growth and proliferation and functions as a transcription factor, a transcriptional coregulator, and in cytoplasmic signalling. The diverse roles of the ER include effects on e.g. bone, endometrium, ovaries, and mammary epithelium. The ER is a key biomarker in clinical management of breast cancer, where it is used as a prognostic and treatment-predictive factor, and a therapeutical target. Several functionally distinct ER isoforms have been described, but current transcript annotation in public databases is incomplete and inconsistent. We analysed short- and long-read RNA sequencing data from breast tumours, breast cancer cell lines, and normal tissues to create a comprehensive annotation of ER transcripts and combined it with experimental studies of full-length protein and six alternative isoforms to compare transcription factor activity, subcellular localisation, and response to the ER-targeting drug fulvestrant. Antibodies differ in ability to detect alternative isoforms, which raises concerns for the interpretation of ER-status in routine pathology. Future work should investigate the effects of alternative isoforms on patient survival and therapy response. An accurate annotation of ER isoforms will aid in interpretation of clinical data and inform functional studies to improve our understanding of the ER in health and disease.

2023-09-20 | GSE208238 | GEO

Two functionally distinct human Pan3 isoforms regulate mRNA turnover across the transcriptome

Project description:Human Pan3 protein has two functionally distinct isoforms required for proper decay of mRNA across the transcriptome.

2018-02-14 | GSE86549 | GEO

Estrogen regulation and physiopathologic significance of alternative promoters in breast cancer

Project description:Alternative promoters (APs) occur in >30% protein-coding genes and contribute to proteome diversity. However, large-scale analyses of AP regulation are lacking, and little is known about their potential physiopathologic significance. To better understand the transcriptomic impact of estrogens, which play a major role in breast cancer, we analyzed gene and AP regulation by estradiol in MCF7 cells using pan-genomic exon arrays. We thereby identified novel estrogen-regulated genes, and determined the regulation of AP-encoded transcripts in 150 regulated genes. In <30% cases, APs were regulated in a similar manner by estradiol, while in >70% cases, they were regulated differentially. The patterns of AP regulation correlated with the patterns of estrogen receptor (ERα) and CCCTC-binding factor (CTCF) binding sites at regulated gene loci. Interestingly, among genes with differentially regulated APs, we identified cases where estradiol regulated APs in an opposite manner, sometimes without affecting global gene expression levels. This promoter switch was mediated by the DDX5/DDX17 family of ERα coregulators. Finally, genes with differentially regulated promoters were preferentially involved in specific processes (e.g., cell structure and motility, and cell cycle). We show in particular that isoforms encoded by the NET1 gene APs, which are inversely regulated by estradiol, play distinct roles in cell adhesion and cell cycle regulation, and that their expression is differentially associated with prognosis in ER+ breast cancer. Altogether, this study identifies the patterns of AP regulation in estrogen-regulated genes, demonstrates the contribution of AP-encoded isoforms to the estradiol-regulated transcriptome, as well as their physiopathologic significance in breast cancer.

2010-02-17 | GSE20342 | GEO

Alternative promoters and splicing create multiple functionally distinct isoforms of oestrogen receptor alpha in breast cancer and healthy tissues.

Project description:BackgroundOestrogen receptor alpha (ER) is involved in cell growth and proliferation and functions as a transcription factor, a transcriptional coregulator, and in cytoplasmic signalling. It affects, for example, bone, endometrium, ovaries and mammary epithelium. It is a key biomarker in clinical management of breast cancer, where it is used as a prognostic and treatment-predictive factor, and a therapeutical target. Several ER isoforms have been described, but transcript annotation in public databases is incomplete and inconsistent, and functional differences are not well understood.MethodsWe have analysed short- and long-read RNA sequencing data from breast tumours, breast cancer cell lines, and normal tissues to create a comprehensive annotation of ER transcripts and combined it with experimental studies of full-length protein and six alternative isoforms.ResultsThe isoforms have varying transcription factor activity, subcellular localisation, and response to the ER-targeting drugs tamoxifen and fulvestrant. Antibodies differ in ability to detect alternative isoforms, which raises concerns for the interpretation of ER-status in routine pathology.ConclusionsFuture work should investigate the effects of alternative isoforms on patient survival and therapy response. An accurate annotation of ER isoforms will aid in interpretation of clinical data and inform functional studies to improve our understanding of the ER in health and disease.

| S-EPMC10557849 | biostudies-literature

Chromatin-dependent cryptic promoters encode alternative protein isoforms in yeast

Project description:Chromatin-dependent cryptic promoters encode alternative protein isoforms in yeast

| PRJNA488219 | ENA

Progesterone Receptor Isoforms, Agonists and Antagonists Differentially Reprogram Estrogen Signaling.

Project description:Progesterone Receptor Isoforms, Agonists and Antagonists Differentially Reprogram Estrogen Signaling.

| PRJNA319518 | ENA

Differential effects of estrogen receptor beta isoforms on glioblastoma progression

Project description:Differential effects of estrogen receptor beta isoforms on glioblastoma progression

| PRJNA412261 | ENA

Localization of functionally distinct CDC42 isoforms in neurons requires alternative 3'UTR usage

Project description:The proper subcellular localization of RNAs and local translational regulation is crucial in highly compartmentalized cells, such as neurons. RNA localization is mediated by specific cis-regulatory elements usually found in mRNA 3'UTRs. Therefore, processes that generate alternative 3'UTRs – alternative splicing and polyadenylation – have the potential to diversify mRNA localization patterns in neurons. Here, we performed mapping of alternative 3'UTRs in neurites and soma isolated from mESC-derived neurons. Our analysis identified 593 genes with differentially localized 3'UTR isoforms. In particular, we have shown that two isoforms of Cdc42 gene with distinct functions in neuronal polarity are differentially localized between neurites and soma of mESC-derived and mouse primary cortical neurons, at both mRNA and protein level. Using reporter assays and 3'UTR swapping experiments, we have identified the role of alternative 3’UTRs and mRNA transport in differential localization of alternative CDC42 protein isoforms. Moreover, we used SILAC to identify isoform-specific Cdc42 3'UTR-bound proteome with potential role in Cdc42 localization and translation. Our analysis points to usage of alternative 3'UTR isoforms as a novel mechanism to provide for differential localization of functionally diverse alternative protein isoforms.

2018-12-07 | PXD011518 | Pride

Chromatin-dependent cryptic promoters encode alternative protein isoforms in yeast

Project description:Cryptic transcription is widespread and generates a heterogeneous group of RNA molecules of unknown function. To improve our understanding of cryptic transcription, we investigated their transcription start site usage, chromatin organization and post-transcriptional consequences in Saccharomyces cerevisiae. We show that transcription start sites of chromatin-dependent internal cryptic transcripts resemble those of protein coding genes in terms of DNA sequence, directionality and chromatin accessibility. We define the 5’ and 3’ boundaries of cryptic transcripts and show that, contrary to RNA degradation-dependent ones , they often overlap with the end of the gene thereby using the canonical polyadenylation site and associate to polyribosomes. In fact, we show that chromatin-dependent cryptic transcripts can be recognized by ribosomes and may produce truncated polypeptides from downstream, in-frame start codons. Our work suggests that a significant fraction of chromatin-dependent internal cryptic promoters are in fact alternative truncated mRNA isoforms. The expression of these chromatin-dependent isoforms is conserved from yeast to human expanding the functional consequences of cryptic transcription and proteome complexity.

2019-10-01 | GSE119114 | GEO

Postrecruitment Regulation of RNA Pol II Directs Rapid Signaling Responses at the Promoters of Estrogen Target Genes

Project description:Under current models for signal-dependent transcription in eukaryotes, DNA-binding activator proteins regulate the recruitment of RNA polymerase II (Pol II) to a set of target promoters. Yet, recent studies, as well as our results herein, show that Pol II is widely distributed (i.e., "preloaded") at the promoters of many genes prior to specific signaling events. How Pol II recruitment and Pol II preloading fit within a unified model of gene regulation is unclear. In addition, the mechanisms through which cellular signals activate preloaded Pol II across mammalian genomes remain largely unknown. Here we show that the predominant genomic outcome of estrogen signaling is the post-recruitment regulation of Pol II activity through phosphorylation, rather than recruitment of Pol II. Furthermore, we show that negative elongation factor (NELF) binds to estrogen target promoters in conjunction with preloaded Pol II and represses gene expression until the appropriate signal is received. Finally, our studies reveal that the estrogen-dependent activation of preloaded Pol II facilitates rapid transcriptional and post-transcriptional responses which play important physiological roles in regulating estrogen signaling itself. Our results reveal a broad use of post-recruitment Pol II regulation by the estrogen signaling pathway, a mode of regulation that is likely to apply to a wide variety of signal-regulated pathways. ChIP-chip analysis for RNA Pol II, Ser5 phosphorylated RNA Pol II and NELF-A in MCF7 breast cancer cells.

2010-05-14 | E-GEOD-13051 | biostudies-arrayexpress

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