H3K27ac HiChIP in prostate cell lines identifies risk genes for prostate cancer susceptibility.

Cell Line, Tumor Chromatin Immunoprecipitation Sequencing Chromosomes, Human Clustered Regularly Interspaced Short Palindromic Repeats Genetic Predisposition to Disease Genetic Techniques Genome-Wide Association Study Histone Code / genetics Humans Male Prostatic Neoplasms / genetics Quantitative Trait Loci
CRISPRi GWAS HiChIP PrCa risk loci eQTL

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
02 12 2021
Historique:
received: 02 04 2021
accepted: 02 11 2021
pubmed: 26 11 2021
medline: 29 12 2021
entrez: 25 11 2021
Statut: ppublish

Résumé

Genome-wide association studies (GWASs) have identified more than 200 prostate cancer (PrCa) risk regions, which provide potential insights into causal mechanisms. Multiple lines of evidence show that a significant proportion of PrCa risk can be explained by germline causal variants that dysregulate nearby target genes in prostate-relevant tissues, thus altering disease risk. The traditional approach to explore this hypothesis has been correlating GWAS variants with steady-state transcript levels, referred to as expression quantitative trait loci (eQTLs). In this work, we assess the utility of chromosome conformation capture (3C) coupled with immunoprecipitation (HiChIP) to identify target genes for PrCa GWAS risk loci. We find that interactome data confirm previously reported PrCa target genes identified through GWAS/eQTL overlap (e.g., MLPH). Interestingly, HiChIP identifies links between PrCa GWAS variants and genes well-known to play a role in prostate cancer biology (e.g., AR) that are not detected by eQTL-based methods. HiChIP predicted enhancer elements at the AR and NKX3-1 prostate cancer risk loci, and both were experimentally confirmed to regulate expression of the corresponding genes through CRISPR interference (CRISPRi) perturbation in LNCaP cells. Our results demonstrate that looping data harbor additional information beyond eQTLs and expand the number of PrCa GWAS loci that can be linked to candidate susceptibility genes.

Identifiants

DOI: 10.1016/j.ajhg.2021.11.007 PMID: 34822763 PMC: PMC8715276
pubmed: 34822763
pii: S0002-9297(21)00419-5
doi: 10.1016/j.ajhg.2021.11.007
pmc: PMC8715276
pii:
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

2284-2300

Subventions

Organisme : NINDS NIH HHS
ID : T32 NS048004
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258808
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA251555
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244569
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227237
Pays : United States

Informations de copyright

Copyright © 2021. Published by Elsevier Inc.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare no competing interests.

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Auteurs

Claudia Giambartolomei (C)

Central RNA Lab, Istituto Italiano di Tecnologia, Genova 16163, Italy; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Ji-Heui Seo (JH)

Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215, USA; The Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, MA 02215, USA.

Tommer Schwarz (T)

Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Malika Kumar Freund (MK)

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Ruth Dolly Johnson (RD)

Department of Computer Science, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Sandor Spisak (S)

Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215, USA.

Sylvan C Baca (SC)

Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215, USA.

Alexander Gusev (A)

Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215, USA.

Nicholas Mancuso (N)

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90032, USA.

Bogdan Pasaniuc (B)

Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Johnson Comprehensive Cancer Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: pasaniuc@ucla.edu.

Matthew L Freedman (ML)

Department of Medical Oncology, The Center for Functional Cancer Epigenetics, Dana Farber Cancer Institute, Boston, MA 02215, USA; The Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: mfreedman@partners.org.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Techniques d'investigation › Techniques immunologiques › Immunoprécipitation › Immunoprécipitation de la chromatine › Séquençage après immunoprécipitation de la chromatine › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Chromosomes › Chromosomes de mammifère › Chromosomes humains › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Séquences répétées en tandem › Clustered regularly interspaced short palindromic repeats › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Code histone › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › H3K27ac HiChIP in prostate cell lines...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Locus de caractère quantitatif › H3K27ac HiChIP in prostate cell lines...