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Metadata Commons Identifier

HMC000117

Project Title

Decoding the Epigenetics and Chromatin Loop Dynamics of Androgen Receptor-Mediated Transcription

Project Description

Androgen receptor (AR)-mediated transcription plays a critical role in normal prostate development and prostate cancer growth. AR drives gene expression by binding to thousands of cis-regulatory elements (CRE) that loop to hundreds of target promoters. With multiple CREs interacting with a single promoter, it remains unclear how individual AR bound CREs contribute to gene expression. To characterize the involvement of these CREs, we investigated the AR-driven epigenetic and chromosomal chromatin looping changes. We collected a kinetic multi-omic dataset comprised of steady-state mRNA, chromatin accessibility, transcription factor binding, histone modifications, chromatin looping, and nascent RNA. Using an integrated regulatory network, we found that AR binding induces sequential changes in the epigenetic features at CREs, independent of gene expression. Further, we showed that binding of AR does not result in a substantial rewiring of chromatin loops, but instead increases the contact frequency of pre-existing loops to target promoters. Our results show that gene expression strongly correlates to the changes in contact frequency. We then proposed and experimentally validated an unbalanced multi-enhancer model where the impact on gene expression of AR-bound enhancers is heterogeneous, and is proportional to their contact frequency with target gene promoters. Overall, these findings provide new insight into AR-mediated gene expression upon acute androgen simulation and develop a mechanistic framework to investigate nuclear receptor mediated perturbations.Time-course multi-omics data analysis: GEO SuperSeries <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251898">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251898</a> <ul><li>ChIP-seq: <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251894">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251894</a> - LNCaP AR, FOXA1, H3K27ac & H3K4me3 Chromatin Immunoprecipitation (ChIP-seq) upon dihydrotestosterone (DHT) treatment</li><li>HiChIP-seq: <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251895">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251895</a> - HiC combined with capture ChIP-seq (HiChIP) for acute androgen treatment on LNCaP cells</li><li>Start-seq: <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251897">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251897</a> - Small Capped Nascent RNA Sequencing (Start-seq) for acute androgen treatment on LNCaP cells</li><li>RNA-seq: <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251896">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251896</a>  - RNA Sequencing for acute androgen treatment on LNCaP cells</li><li>ATAC-seq: <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251893">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE251893</a> - Assay for transposase-accessible chromatin with sequencing (ATAC-seq) for acute androgen treatment on LNCaP cells</li></ul>

Project Funder(s)

Canadian Institutes of Health Research (CIHR), TÜBİTAK , United States Department of Defense (DOD), Claudia Adams Barr Program for Innovative Cancer Research, Dana-Farber Cancer Institute Presidential Initiatives Fund, H.L. Snyder Medical Research Foundation, Cutler Family Fund for Prevention and Early Detection, the Donahue Family Fund, NIH Awards, a Movember PCF Challenge Award

Project Institution(s)

Vancouver Prostate Centre

Project Investigator(s)

Umut Berkay Altintas, Nathan Lack, Matthew Freedman, Ji-Heui Sao

Data Access Request URL*

Keywords

LNCaP, Chromatin Conformation, HiChIP, enhancer, ChIP-seq, chromatin accessibility, FOXA1

Publication Link

https://pubmed.ncbi.nlm.nih.gov/39489778

Study Completed

Post to REACH BC Platform

Cohort Name

LNCaP cell line

Cohort Size

Disease/Condition Studied

prostate cancer

Enrollment Time Window

Biobanking Consent Available

Medical History Available

Ethnicity Availability

Time Course

Patient Phenotypes

Patient Outcomes

Clinical Data Types Available

Time Course Data Points

0m, 30min, 4h, 16h, 72h

Enrollment City

Groups

Project

Cohort

Enrollment City

Groups

Samples and Omics