Motif-based model of transcription predicts effects of sequence variants in AR enhancers and reveals distinct functions for AR-associated transcription factors
Taeb, H.; Safaeesirat, A.; Tekoglu, E.; Xiao, K.; Huang, C.-C. F.; Lack, N. A.; Emberly, E. · genomics · 2026-09-07 · 原文
DOI：10.64898/2026.09.02.748967作者：7 位
Androgen receptor (AR)-mediated transcription plays a central role in prostate cancer development and progression, yet the contributions of individual transcription factors (TFs) to AR-dependent enhancer activity remain incompletely understood. Here we use a biophysically motivated, interpretable motif-based model to dissect these contributions from STARR-seq data in LNCaP cells. By fitting the model separately to androgen inducibility and to baseline enhancer activity, we resolve TFs into three functional classes: hormone-dependent drivers, constitutive activators, and dual-role factors that contribute to both. These patterns suggest that inducibility is associated not only with the presence of AR and co-activator motifs, but also with the relative absence of constitutive activators that may saturate enhancer output. We validate the model against an independent saturation-mutagenesis dataset spanning 40 AR enhancers, predicting mutational effects at single-base resolution (AUC = 0.76), and show that direct fitting to these data independently recovers known AR regulators. Finally, we apply the model to prostate cancer GWAS risk alleles in AR binding site regions, prioritizing four
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1. 人话版
Androgen receptor (AR)-mediated transcription plays a central role in prostate cancer development and progression, yet the contributions of individual transcription factors (TFs) to AR-dependent enhancer activity remain incompletely understood.
Here we use a biophysically motivated, interpretable motif-based model to dissect these contributions from STARR-seq data in LNCaP cells.
2. 领域脉络
本文类目：genomics，属于其所在研究脉络的最新进展。
3. 机制拆解
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4. 证据与数字
We validate the model against an independent saturation-mutagenesis dataset spanning 40 AR enhancers, predicting mutational effects at single-base resolution (AUC = 0.76), and show that direct fitting to these data independently recovers known AR regulators.
5. 反例与边界
By fitting the model separately to androgen inducibility and to baseline enhancer activity, we resolve TFs into three functional classes: hormone-dependent drivers, constitutive activators, and dual-role factors that contribute to both.
These patterns suggest that inducibility is associated not only with the presence of AR and co-activator motifs, but also with the relative absence of constitutive activators that may saturate enhancer output.
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