Research Project: Swi/Snf Kromatin Yeniden-Modelleyici Kompleksinin Hoxb13 Tarafından Rekrutmanı Ve Prostat Kanseri Epigenetigine Etkisi
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Contributors
Funders
ID
TB.00659
Authors
Lack, Nathan Alan
Faculty Member
Publications
Comprehensive functional annotation of ESR1-driven enhancers in breast cancer reveals hierarchical activity independent of genomic and epigenomic contexts
(Cold Spring Harbor Lab Press, Publications Dept, 2025) Yapıcı, Elif; Lack, Nathan Alan; Korkmaz, Gözde; Zekri, Yanis; Gregoricchio, Sebastian; Huang, Chia-Chi Flora; Morova, Tunc; Altintas, Umut Berkay; Zwart, Wilbert; School of Medicine; KUTTAM (Koç University Research Center for Translational Medicine); Yes; Yapıcı, Elif; SCHOOL OF MEDICINE; Research Center
Estrogen receptor 1 (ESR1; also known as ER alpha, encoded by ESR1 gene) is the driving transcription factor in breast cancer development and progression. ESR1 genomic action is thought to operate under tight epigenetic control, with its chromatin binding and subsequent transcriptional output heavily reliant on the pioneer transcription factor FOXA1, which renders chromatin accessible for ESR1 binding. However, the exact contribution of the epigenome to selective enhancer activation by ESR1 remains to be fully elucidated. To address this, we employ a massively parallel reporter assay to profile 7576 individual ESR1 binding sites for hormone responsiveness. Only a minority of ESR1-occupied enhancers exhibit hormone-induced activity. These findings are confirmed by genomic data in situ, indicating that enhancer activation within a chromatinized context is robustly captured in a plasmid-based reporter assay. In silico integration of our findings with publicly available functional genomics data sets from breast cancer cell lines and tumor samples reveal distinct transcription complex compositions, 3D genome contexts, and regulatory dynamics associated with different classes of ESR1 binding sites. Overall, our results establish a comprehensive framework to highlight and elucidate the molecular basis underlying ESR1 genomic heterogeneity and its contribution to breast cancer biology and clinical outcomes.
Distinct transcription factor interactions drive HOXB13 activity in different stages of prostate cancer
(National Academy of Sciences, 2025) Ersoy, Betül; Cingöz, Ahmet; Tekoğlu, Tahsin Emirhan; Kulaç, İbrahim; Önder, Tuğba Bağcı; Lack, Nathan Alan; Ersoy, Betül; Tekoğlu, Tahsin Emirhan; Lingadahalli, Shreyas; Altintaş, Umut Berkay; Yu, Ivan Pak Lok; Dikbas, Meric; Missaghimamaghani, Olka; Yavuz, Kerim; Adomat, Hans H.; Morova, Tunç; Xiao, Kevin; Gleave, Martin E.; Fazli, Ladan; Cejas, Paloma; Cherkasov, Artem R. ; Zwart, Wilbert T. ; Haffner, Michael Christoph; Long, Henry W.; Collins, Colin C. ; KUTTAM (Koç University Research Center for Translational Medicine); School of Medicine; Yes; Research Center; SCHOOL OF MEDICINE
HOXB13 is a lineage-specific transcription factor that plays a critical role in initiation and progression of prostate cancer (PCa). While most research has focused on the role of HOXB13 on androgen receptor (AR) activity, here we demonstrate that HOXB13 is frequently expressed in AR-negative tumors and is essential for the proliferation of both AR-positive and -negative PCa models. Strikingly, HOXB13 is remarkably selective and has almost no effect on nonprostatic tissues. Despite this common essentiality in PCa, HOXB13 activity is markedly different in AR-negative stem cell–like tumors, where interactions with the AP-1 change the HOXB13 cistrome and interactome. Yet despite these distinct activities, HOXB13 activity is commonly mediated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. The HOXB13/SMARCD2 interaction alters chromatin accessibility at HOXB13-binding sites, causing increased proliferation in AR-negative PCa. Overall, this work demonstrates a distinct mechanism of action for HOXB13 and highlights its critical role in AR-negative castration-resistant PCa. © © 2025 the Author(s).
