PXD023026

PXD023026 is an original dataset announced via ProteomeXchange.

Title	MCRS1 is a histone acetylation regulator whose loss in hepatocytes promotes cirrhosis
Description	Cirrhosis is a late stage of fibrosis that fatally impairs liver function. Unfortunately, genetic animal models mimicking human cirrhosis are lacking and the molecular mechanisms remain unknown. Here we report the first murine genetic model recapitulating clinical features of cirrhosis, which are induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of the non-specific lethal (NSL) and INO80 chromatin modifier complexes. Deregulation of bile acid (BA) transporter expression, revealed by proteomic analysis of MCRS1-depleted mouse livers, with pronounced downregulation of the Na+-taurocholate cotransporting polypeptide (NTCP), causes BA accumulation in liver sinusoids. Genetic ablation of the BA receptor FXR in hepatic stellate cells (HSCs) suppresses bile duct ligation (BDL)-induced fibrosis in mice. Moreover, in vitro experiments demonstrate that fibrotic marker expression is reduced in FXR-depleted HSCs cultured in conditioned medium containing high BAs from MCRS1-depleted hepatocytes. Additionally, hepatocytic MCRS1 overexpression increases their NTCP levels, and consequently protects mice against BDL-induced liver fibrosis. Deletion of a putative SANT domain in MCRS1, also revealed by protein sequence analysis and essential for histone H3 (H3) binding, disrupts H3/HDAC1 complex formation. This evicts MCRS1 and HDAC1 from their H3 anchoring sites and increases histone lysine acetylation of BA transporter genes, independently of the NSL or INO80 complexes. Taken together, our data reveal a previously unrecognized function of MCRS1 as a novel histone acetylation regulator that binds to H3, and recruits a novel chromatin-modifying complex that maintains gene expression homeostasis and liver health. Accordingly, loss of nuclear MCRS1 correlates with increased histone acetylation in human cirrhosis samples. Regulation of histone acetylation might thus be central to cirrhotic development.
HostingRepository	PRIDE
AnnounceDate	2022-05-19
AnnouncementXML	Submission_2022-05-19_13:11:49.204.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eduardo Zarzuela
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-09 11:22:19	ID requested
⏵ 1	2022-05-19 13:11:50	announced

Garrido A, Kim E, Teijeiro A, S, á, nchez S, á, nchez P, Gallo R, Nair A, Matamala Montoya M, Perna C, Vicent GP, Mu, ñ, oz J, Campos-Olivas R, Melms JC, Izar B, Schwabe RF, Djouder N, Histone acetylation of bile acid transporter genes plays a critical role in cirrhosis. J Hepatol, 76(4):850-861(2022) [pubmed]

submitter keyword: MCRS1, hepatocytes, iTRAQ

Javier Muñoz
contact affiliation	Proteomics Core Unit, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
contact email	jmunozpe@cnio.es
lab head
Eduardo Zarzuela
contact affiliation	Centro Nacional de Investigaciones Oncológicas
contact email	eduzarfer@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023026
     1. Label: PRIDE project
     2. Name: MCRS1 is a histone acetylation regulator whose loss in hepatocytes promotes cirrhosis