Dataset Information

FGF2 antiproliferative stimulus triggers proteomic and transcriptional changes associated with nucleolar disorganization in K-ras-driven mouse tumor cells (Nucleoli TMT)

ABSTRACT: Chromatin plays a crucial role in the intermediation between cell signaling and gene expression. The nucleolus is sensitive to stress and can orchestrate a chain of cellular events in response to stress signals. Despite being a growth factor, FGF2 has anti-proliferative and tumor-suppressive functions in some cellular contexts. In this work, we investigated how the antiproliferative effect of FGF2 modulates chromatin, nucleolus, and rDNA-associated proteins. The chromatin and nucleolar proteome indicated that FGF2 stimulation modulates proteins related to transcription regulation, particularly rRNA expression, and chromatin remodeling proteins. Upon 24 hrs of FGF2 stimulation, the global transcriptional rate and nucleolus area increased in associationalong with intense nucleolar disorganization detected by fibrillarin dispersion and electron microscopy analyses. We confirmed that FGF2 stimulation induced immature rRNA accumulation by increasing rRNA transcription regardless of changes in ribosome profiling. The rDNA-associated protein analysis reinforced that FGF2 stimulus interferes with transcription and rRNA processing/modification, since the proteins Nolc1 and Tcof1 are were upregulated after FGF2 stimulation. Changes in rRNA expression may be crucial for triggering the antiproliferative effect induced by FGF2 since inhibiting RNA Pol I, responsible for rRNA expression, partially reversed the growth arrest induced by FGF2. Taken together, we demonstrate that the antiproliferative FGF2 stimulus triggers significant transcriptional changes, and modulation modulates of the main cell transcription site, the nucleolus, directly modulating the proteome of the rDNA loci.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Julia Pinheiro Chagas da Cunha

PROVIDER: MSV000090518 | MassIVE | Wed Oct 12 11:34:00 BST 2022

SECONDARY ACCESSION(S): PXD037339

REPOSITORIES: MassIVE

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Publications

The antiproliferative effect of FGF2 in K-Ras-driven tumor cells involves modulation of rRNA and the nucleolus.

de Luna Vitorino Francisca N FN Levy Michaella J MJ Mansano Wailemann Rosangela A RA Lopes Mariana M Silva Mariana Loterio ML Sardiu Mihaela E ME Garcia Benjamin A BA Machado Motta Maria Cristina MC Oliveira Carla Columbano CC Armelin Hugo Aguirre HA Florens Laurence A LA Washburn Michael P MP Pinheiro Chagas da Cunha Julia J

Journal of cell science 20231130 22

The nucleolus is sensitive to stress and can orchestrate a chain of cellular events in response to stress signals. Despite being a growth factor, FGF2 has antiproliferative and tumor-suppressive functions in some cellular contexts. In this work, we investigated how the antiproliferative effect of FGF2 modulates chromatin-, nucleolus- and rDNA-associated proteins. The chromatin and nucleolar proteome indicated that FGF2 stimulation modulates proteins related to transcription, rRNA expression and ...[more]

PMID: 37921359

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Project description:Transcription of the several hundred of mouse and human Ribosomal RNA (rRNA) genes accounts for the majority of RNA synthesis in the cell nucleus and is the determinant of cytoplasmic ribosome abundance, a key factor in regulating gene expression. The rRNA genes, referred to globally as the rDNA, are clustered as direct repeats at the Nucleolar Organiser Regions, NORs, of several chromosomes, and in many cells the active repeats are transcribed at near saturation levels. The rDNA is also a hotspot of recombination and chromosome breakage, and hence understanding its control has broad importance. Despite the need for a high level of rDNA transcription, typically only a fraction of the rDNA is transcriptionally active, and some NORs are permanently silenced by CpG methylation. Various chromatin-remodelling complexes have been implicated in counteracting silencing to maintain rDNA activity. However, the chromatin structure of the active rDNA fraction is still far from clear. Here we have combined a high-resolution ChIP-Seq protocol with conditional inactivation of key basal factors to better understand what determines active rDNA chromatin. The data resolve questions concerning the interdependence of the basal transcription factors, show that preinitiation complex formation is driven by the architectural factor UBF (UBTF) independently of transcription, and exclude a significant role for termination by a torpedomechanism. They further reveal the existence of an asymmetric Boundary Complex formed by CTCF, Cohesin and three phased nucleosomes lying adjacent to the rDNA Enhancer and an arrested RNA Polymerase I complex. We find that this complex is the only site of active histone modification in the whole 45kbp rDNA repeat. Strikingly, the Enhancer Boundary Complex not only delimits each functional rRNA gene, but also is stably maintained after gene inactivation and the re-establishment of surrounding repressive chromatin. Our data define the poised state of rDNA chromatin and place the Enhancer Boundary Complex as the likely entry point for the chromatin remodelling complexes.

Dataset Information

FGF2 antiproliferative stimulus triggers proteomic and transcriptional changes associated with nucleolar disorganization in K-ras-driven mouse tumor cells (Nucleoli TMT)

Publications

The antiproliferative effect of FGF2 in K-Ras-driven tumor cells involves modulation of rRNA and the nucleolus.

Similar Datasets

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