Researcher:
Altıntaş, Umut Berkay

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Master Student

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Umut Berkay

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Altıntaş

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Altıntaş, Umut Berkay

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2021 - 20233

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    Dynamic phase separation of the androgen receptor and its coactivators key to regulate gene expression
    (Oxford Univ Press, 2023) 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; N/A; N/A; Altıntaş, Umut Berkay; Lack, Nathan Alan; Master Student; Faculty Member; Graduate School of Sciences and Engineering; School of Medicine; N/A; 120842
    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.
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    PublicationOpen Access
    Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential
    (Nature Portfolio, 2022) Kneppers, J.; Severson, T.M.; Siefert, J.C.; Schol, P.; Joosten, S.E.P.; Yu, I.P.L.; Huang, C.F.; Morova, T.; Giambartolomei, C.; Seo, J.H.; Baca, S.C.; Carneiro, I.; Emberly, E.; Pasaniuc, B.; Jerónimo, C.; Henrique, R.; Freedman, M.L.; Wessels, L.F.A.; Bergman, A.M.; Zwart, W.; N/A; Lack, Nathan Alan; Altıntaş, Umut Berkay; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Graduate School of Sciences and Engineering; 120842; N/A
    Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients’ outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.
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    PublicationOpen Access
    Functional mapping of androgen receptor enhancer activity
    (BioMed Central, 2021) Huang, Flora Chia-Chi; Morova, Tunç; Hu, Eugene; Yu, Lok Pak Ivan; Linder, Simon; Hoogstraat, M.; Stelloo, Suzan; Sar, Funda; Van der Poel, Henk; Saffarzadeh, Mohammadali; Le Bihan, Stephane; McConegy, Brian; Y Feng, Felix; Gleave, E. Martin; Bergman, M. Andries; Collins, Colin; Hach, Faraz; Zwart, Wilbert; Emberly, Eldon; N/A; Department of Molecular Biology and Genetics; Özturan, Doğancan; Altıntaş, Umut Berkay; Gökbayrak, Bengül; Lack, Nathan Alan; PhD Student; Faculty Member; Department of Molecular Biology and Genetics; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); Graduate School of Health Sciences; Graduate School of Sciences and Engineering; N/A; N/A; N/A; 120842
    Background: androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10-100x more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results: to characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions: using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.