PXD060446

PXD060446 is an original dataset announced via ProteomeXchange.

Title	Effects of cis-regulatory elements on proteome
Description	Background Genomic variations contribute to the phenotypic diversity of individuals. A number of polymorphisms in protein-coding regions that alter drug efficacy or lead to adverse reactions have been characterized; however, noncoding regions that affect drug responses are largely overlooked, except for a limited number of well-studied enhancers. Results We conducted a quantitative assessment of cis-regulatory elements (CREs) based on transcription initiation profiling of mRNAs and noncoding RNAs, including enhancer RNAs, by using CAGE (Cap Analysis of Gene Expression). Candidate CREs identified in a hepatocellular carcinoma HepG2 cell line with stable expression of drug-responsive transcription factor pregnane X receptor (PXR) were further narrowed down by integrating data of PXR-binding sites in human primary hepatocytes and genome-wide association studies. We found more than 100-fold enrichments of the candidates to genetically associated loci with circulating levels of bilirubin and vitamin D, which implicated a link to adverse reactions of PXR ligands. We uncovered novel enhancers of UGT1A1 and TSKU through CRISPR/Cas9 knockout experiments. We identified alleles altering regulatory activities of UGT1A1 and CYP24A1enhancers by using luciferase reporter assay. Furthermore, our siRNA experiments revealed an unexpected impact of TSKU on the expression of vitamin D-metabolizing enzymes. Conclusions Our transcriptome-based assessment of CREs expanded the list of drug-inducible and PXR-mediated enhancers and super-enhancers. We identified regulatory alleles that alter drug-induced gene expressions, and discovered a novel molecular cascade associated with an adverse reaction. Our results contribute a precise understanding of the noncoding elements of the human genome underlying drug responses.
HostingRepository	PRIDE
AnnounceDate	2025-04-17
AnnouncementXML	Submission_2025-04-16_23:43:01.242.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tomoe Nishimura
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-03 18:26:03	ID requested
⏵ 1	2025-04-16 23:43:01	announced

Dataset with its publication pending

submitter keyword: Human, DIA, hepatocyte, LC-MS/MS

Hideya Kawaji
contact affiliation	Research Center for Genome & Medical Sciences, Tokyo Metropolitan Institute of Medical Science
contact email	kawaji-hd@igakuken.or.jp
lab head
Tomoe Nishimura
contact affiliation	Tokyo metropolitan institute of medical science
contact email	nishimura-tm@igakuken.or.jp
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD060446
     1. Label: PRIDE project
     2. Name: Effects of cis-regulatory elements on proteome