Research Project: Prostat Kanserinde Androjen Reseptörünün Bağlandığı Arttırıcı (Echancer) Bölgelerinin "Nükleotit Kodu"nun Çözülmesi
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Contributors
Funders
ID
TB.00467
Authors
Lack, Nathan Alan
Faculty Member
Publications
Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression
(Oxford Univ Press, 2023) Altıntaş, Umut Berkay; Lack, Nathan Alan; Zhang, Fan; Biswas, Maitree; Massah, Shabnam; Lee, Joseph; Lingadahalli, Shreyas; Wong, Samantha; Wells, Christopher; Foo, Jane; Khan, Nabeel; Morin, Helene; Saxena, Neetu; Kung, Sonia H. Y.; Sun, Bei; Nunez, Ana Karla Parra; Sanchez, Christophe; Chan, Novia; Ung, Lauren; Bui, Jennifer M.; Wang, Yuzhuo; Fazli, Ladan; Oo, Htoo Zarni; Rennie, Paul S.; Cherkasov, Artem; Gleave, Martin E.; Gsponer, Jorg; Lallous, Nada; School of Medicine; Graduate School of Sciences and Engineering; Yes; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING; SCHOOL OF MEDICINE
Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.
Androgen receptor-mediated transcription in prostate cancer
(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Lack, Nathan Alan; Özturan, Doğancan; Morova, Tunç; Department of Computer Engineering; Department of Chemical and Biological Engineering; KUTTAM (Koç University Research Center for Translational Medicine); School of Medicine; Yes; College of Engineering; Research Center; SCHOOL OF MEDICINE
Androgen receptor (AR)-mediated transcription is critical in almost all stages of prostate cancer (PCa) growth and differentiation. This process involves a complex interplay of coregulatory proteins, chromatin remodeling complexes, and other transcription factors that work with AR at cis-regulatory enhancer regions to induce the spatiotemporal transcription of target genes. This enhancer-driven mechanism is remarkably dynamic and undergoes significant alterations during PCa progression. In this review, we discuss the AR mechanism of action in PCa with a focus on how cis-regulatory elements modulate gene expression. We explore emerging evidence of genetic variants that can impact AR regulatory regions and alter gene transcription in PCa. Finally, we highlight several outstanding questions and discuss potential mechanisms of this critical transcription factor.
Optimized high-throughput screening of non-coding variants identified from genome-wide association studies
(Oxford University Press (OUP), 2022) Lack, Nathan Alan; Morova, Tunc; Ding, Yi; Huang, Chia-Chi F.; Sar, Funda; Schwarz, Tommer; Giambartolomei, Claudia; Baca, Sylvan C.; Grishin, Dennis; Hach, Faraz; Gusev, Alexander; Freedman, Matthew L.; Pasaniuc, Bogdan; KUTTAM (Koç University Research Center for Translational Medicine); School of Medicine; Yes; Research Center; SCHOOL OF MEDICINE
The vast majority of disease-associated single nucleotide polymorphisms (SNP) identified from genome-wide association studies (GWAS) are localized in non-coding regions. A significant fraction of these variants impact transcription factors binding to enhancer elements and alter gene expression. To functionally interrogate the activity of such variants we developed snpSTARRseq, a high-throughput experimental method that can interrogate the functional impact of hundreds to thousands of non-coding variants on enhancer activity. snpSTARRseq dramatically improves signal-to-noise by utilizing a novel sequencing and bioinformatic approach that increases both insert size and the number of variants tested per loci. Using this strategy, we interrogated known prostate cancer (PCa) risk-associated loci and demonstrated that 35% of them harbor SNPs that significantly altered enhancer activity. Combining these results with chromosomal looping data we could identify interacting genes and provide a mechanism of action for 20 PCa GWAS risk regions. When benchmarked to orthogonal methods, snpSTARRseq showed a strong correlation with in vivo experimental allelic-imbalance studies whereas there was no correlation with predictive in silico approaches. Overall, snpSTARRseq provides an integrated experimental and computational framework to functionally test non-coding genetic variants.
Dynamic phase separation of the androgen receptor and its coactivators to regulate gene expression
(Amer Assoc Cancer Research, 2022) Altıntaş, Umut Berkay; Lack, Nathan Alan; Zhang, Fan; Biswas, Maitree; Lee, Joseph; Lingadahalli, Shreyas; Wong, Samantha; Wells, Christopher; Saxena, Neetu; Sun, Bei; Parra-Nunez, Ana K.; Sanchez, Christophe; Foo, Jane; Chan, Novia; Ung, Lauren; Khan, Nabeel; Bui, Jennifer M.; Wang, Yuzhuo; Fazli, Ladan; Rennie, Paul S.; Cherkasov, Artem; Gleave, Martin E.; Gsponer, Joerg; Lallous, Nada; School of Medicine; Graduate School of Sciences and Engineering; Yes; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING; SCHOOL OF MEDICINE
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