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Relationship between nucleosome positioning and progesterone-induced alternative splicing in breast cancer cells.

ABSTRACT: Splicing of mRNA precursors can occur cotranscriptionally and it has been proposed that chromatin structure influences splice site recognition and regulation. Here we have systematically explored potential links between nucleosome positioning and alternative splicing regulation upon progesterone stimulation of breast cancer cells. We confirm preferential nucleosome positioning in exons and report four distinct profiles of nucleosome density around alternatively spliced exons, with RNA polymerase II accumulation closely following nucleosome positioning. Hormone stimulation induces switches between profile classes, correlating with a subset of alternative splicing changes. Hormone-induced exon inclusion often correlates with higher nucleosome occupancy at the exon or the preceding intronic region and with higher RNA polymerase II accumulation. In contrast, exons skipped upon hormone stimulation display low nucleosome densities even before hormone treatment, suggesting that chromatin structure primes alternative splicing regulation. Skipped exons frequently harbor binding sites for hnRNP AB, a hormone-induced splicing regulator whose knock down prevents some hormone-induced skipping events. Collectively, our results argue that a variety of chromatin architecture mechanisms can influence alternative splicing decisions.

SUBMITTER: Iannone C

PROVIDER: S-EPMC4338333 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Relationship between nucleosome positioning and progesterone-induced alternative splicing in breast cancer cells.

Iannone Camilla C Pohl Andy A Papasaikas Panagiotis P Soronellas Daniel D Vicent Guillermo P GP Beato Miguel M ValcáRcel Juan J

RNA (New York, N.Y.) 20150301 3

Splicing of mRNA precursors can occur cotranscriptionally and it has been proposed that chromatin structure influences splice site recognition and regulation. Here we have systematically explored potential links between nucleosome positioning and alternative splicing regulation upon progesterone stimulation of breast cancer cells. We confirm preferential nucleosome positioning in exons and report four distinct profiles of nucleosome density around alternatively spliced exons, with RNA polymerase ...[more]

PMID: 25589247

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Project description:Estrogens play an important role in breast cancer (BC) development and progression; when the two isoforms of the estrogen receptor (ER? and ER?) are co-expressed each of them mediate specific effects of these hormones in BC cells. ER? has been suggested to exert an antagonist role toward the oncogenic activities of ER?, and for this reason it is considered an oncosuppressor. As clinical evidence regarding a prognostic role for this receptor subtype in hormone-responsive BC is still limited and conflicting, more knowledge is required on the biological functions of ER? in cancer cells. We have previously described the ER? and ER? interactomes from BC cells, identifying specific and distinct patterns of protein interactions for the two receptors. In particular, we identified factors involved in mRNA splicing and maturation as important components of both ER? and ER? pathways. Guided by these findings, here we performed RNA sequencing to investigate in depth the differences in the early transcriptional events and RNA splicing patterns induced by estradiol in cells expressing ER? alone or ER? and ER?.Exon skipping was the most abundant splicing event in the post-transcriptional regulation by estradiol. We identified several splicing events induced by ER? alone and by ER?+ER?, demonstrating for the first time that ER? significantly affects estrogen-induced splicing in BC cells, as revealed by modification of a subset of ER?-dependent splicing by ER?, as well as by the presence of splicing isoforms only in ER?+cells. In particular, we observed that ER?+BC cell lines exhibited around 2-fold more splicing events than the ER?- cells. Interestingly, we identified putative direct targets of ER?-mediated alternative splicing by correlating the genomic locations of ER? and ER? binding sites with estradiol-induced differential splicing in the corresponding genes.Taken together, these results demonstrate that ER? significantly affects estrogen-induced early transcription and mRNA splicing in hormone-responsive BC cells, providing novel information on the biological role of ER? in these tumors.

Project description:BackgroundAdaptation to low oxygen by changing gene expression is vitally important for cell survival and tissue development. The sprouting of new blood vessels, initiated from endothelial cells, restores the oxygen supply of ischemic tissues. In contrast to the transcriptional response induced by hypoxia, which is mainly mediated by members of the HIF family, there are only few studies investigating alternative splicing events. Therefore, we performed an exon array for the genome-wide analysis of hypoxia-related changes of alternative splicing in endothelial cells.Methodology/principal findingsHuman umbilical vein endothelial cells (HUVECs) were incubated under hypoxic conditions (1% O(2)) for 48 h. Genome-wide transcript and exon expression levels were assessed using the Affymetrix GeneChip Human Exon 1.0 ST Array. We found altered expression of 294 genes after hypoxia treatment. Upregulated genes are highly enriched in glucose metabolism and angiogenesis related processes, whereas downregulated genes are mainly connected to cell cycle and DNA repair. Thus, gene expression patterns recapitulate known adaptations to low oxygen supply. Alternative splicing events, until now not related to hypoxia, are shown for nine genes: six which are implicated in angiogenesis-mediated cytoskeleton remodeling (cask, itsn1, larp6, sptan1, tpm1 and robo1); one, which is involved in the synthesis of membrane-anchors (pign) and two universal regulators of gene expression (cugbp1 and max).Conclusions/significanceFor the first time, this study investigates changes in splicing in the physiological response to hypoxia on a genome-wide scale. Nine alternative splicing events, until now not related to hypoxia, are reported, considerably expanding the information on splicing changes due to low oxygen supply. Therefore, this study provides further knowledge on hypoxia induced gene expression changes and presents new starting points to study the hypoxia adaptation of endothelial cells.

Dataset Information

Relationship between nucleosome positioning and progesterone-induced alternative splicing in breast cancer cells.

Publications

Relationship between nucleosome positioning and progesterone-induced alternative splicing in breast cancer cells.

Similar Datasets

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