PXD036976-1

PXD036976 is an original dataset announced via ProteomeXchange.

Title	Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice
Description	RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein-2 (RBFOX2) in maintaining cholesterol homeostasis in an obesogenic environment in the liver. Using enhanced individual-nucleotide resolution UV-crosslinking and immunoprecipitation (eiCLIP), we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesityinduced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.
HostingRepository	PRIDE
AnnounceDate	2022-11-28
AnnouncementXML	Submission_2022-11-28_02:14:58.065.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	MiguelPrado
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-09-25 14:33:00	ID requested
⏵ 1	2022-11-28 02:14:58	announced

Dataset with its publication pending

submitter keyword: Mouse, cholesterol, liver, splicing

MiguelPrado
contact affiliation	Harvard Medical School, Boston, USA Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
contact email	miguel.prado@ispasturias.es
lab head
MiguelPrado
contact affiliation	Harvard Medical School
contact email	miguel_prado@hms.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD036976
     1. Label: PRIDE project
     2. Name: Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice