PXD047930-1

PXD047930 is an original dataset announced via ProteomeXchange.

Title	FXR controls gene expression independently of RXR at non-canonical response elements
Description	The Farnesoid-X-Receptor (FXR) is a class II nuclear receptor (NR), a class that obligately heterodimerizes with the Retinoid-X-Receptor (RXR). FXR is expressed as 4 isoforms (α1-α4) activated by bile acids that drive transcription from response elements IR-1 (inverted repeat-1). We recently showed that FXR isoforms α2 and α4 bind to non-canonical response elements ER-2 (everted repeat-2), thereby increasing mitochondrial respiratory capacity and limiting de novo lipogenesis. Binding to ER-2 motifs in mouse liver organoids represented 89% of all FXR genome wide binding. However, mechanistic differences in FXR binding and activation from these two response elements remained unexplored. Using DNA pull down followed by mass-spectrometry, we show that RXR is not involved in FXR binding to ER-2 response elements. Instead, RXR inhibited FXR binding and activation from these elements in luciferase reporters. Genome wide, RXR-lacking FXR binding sites showed higher enrichment for ER-2 motifs in mouse liver. Pharmacological and mutational abrogation of FXR-RXR heterodimerization specifically retained ER-2 transactivation capacities in luciferase reporters and HepG2 cells. Transcriptome-wide, 25% of FXR targets were inhibited upon RXR overexpression, but specifically activated by a novel heterodimerization-deficient mutant FXRα2L434R. These genes were ER-2 responsive and were involved in lipid metabolism and ammonia detoxification. In conclusion, we discovered that RXR is not required and even inhibits binding of FXRα2 to ER-2. Thus, whereas FXR α1 and α3 seem to be genuine class II NR, FXRα2 and α4 are facultative class II at ER-2 motifs. This novel feature holds promise to exploit and tailor therapeutic responses to FXR agonism.
HostingRepository	PRIDE
AnnounceDate	2024-11-12
AnnouncementXML	Submission_2024-11-12_05:56:51.610.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jelmer Dijkstra
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-19 01:26:23	ID requested
⏵ 1	2024-11-12 05:56:51	announced

Dataset with its publication pending

submitter keyword: FXR RXR Nuclear Receptor Transcription Regulation MS/MS DNA pulldown

Michiel Vermeulen
contact affiliation	Faculty of Science, Radboud Institute for Molecular Life Sciences, Oncode Institute, Radboud University Nijmegen, Nijmegen, The Netherlands
contact email	mnichiel.vermeulen@ru.nl
lab head
Jelmer Dijkstra
contact affiliation	RIMLS
contact email	jelmer.dijkstra@science.ru.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047930
     1. Label: PRIDE project
     2. Name: FXR controls gene expression independently of RXR at non-canonical response elements