ABI1 regulates transcriptional activity of Androgen Receptor by novel DNA and AR binding mechanism [ChIP-seq]. ABI1 regulates transcriptional activity of Androgen Receptor by novel DNA and AR binding mechanism [ChIP-seq]

Transcription regulates key functions of living organisms in normal and disease states, including cell growth and development, embryonic and adult tissue organization, and tumor progression. Here we identify a novel mechanism of transcriptional regulation by an actin regulatory and signaling protein, Abelson Interactor 1(ABI1). Using prostate cancer models, we uncover a reciprocal regulation between ABI1 and the Androgen Receptor (AR). ABI1 is a direct, androgen-regulated target; in turn, ABI1 interacts with AR and its splice variant ARv7, and co-regulates a subset of specific transcriptional targets. ABI1 directs transcription through transient yet well-defined interaction of its intrinsically disordered region with DNA. Clinical evaluation shows that both the ABI1-DNA binding (through Exon 4 splicing) and ABI1-AR interaction are regulated during androgen deprivation therapy and prostate cancer progression, thus controlling tumor plasticity through connecting actin cytoskeleton and cellular signaling to transcriptional regulation. We propose that ABI1 is an epigenetic regulator of transcriptional homeostasis in AR-driven cancers. Overall design: A ChIP reaction was carried out using 40 ug of each DNA sample with antibodies to either Abi1 (MBL International, D147-3) or AR (N20, Santa Cruz Bio Technology, sc-816). The immunoprecipitated DNA was processed into a standard Illumina ChIP-Seq library and sequenced.

转录调控在正常及疾病状态下调控生物体的核心生命功能，涵盖细胞生长发育、胚胎与成年组织构建以及肿瘤进展过程。本研究发现了一类由肌动蛋白调控与信号转导蛋白Abelson互作蛋白1（Abelson Interactor 1, ABI1）介导的新型转录调控机制。利用前列腺癌模型，我们揭示了ABI1与雄激素受体（Androgen Receptor, AR）之间的双向调控关系：ABI1是直接受雄激素调控的靶基因；反过来，ABI1可与AR及其剪接变体ARv7结合，并共同调控一组特定的转录靶基因。ABI1通过其固有无序区域与DNA形成短暂但明确的相互作用来调控转录。临床评估结果显示，ABI1的DNA结合功能（通过外显子4剪接实现）以及ABI1与AR的相互作用均在雄激素剥夺治疗与前列腺癌进展过程中受到调控，进而通过连接肌动蛋白细胞骨架与细胞信号通路实现对肿瘤可塑性的调控。本研究提出，ABI1是AR驱动型癌症中转录稳态的表观遗传调控因子。实验设计：取每份40 μg的DNA样品，分别使用靶向Abi1的抗体（MBL International, D147-3）或靶向AR的抗体（N20, Santa Cruz Bio Technology, sc-816）进行染色质免疫沉淀（ChIP）反应。将免疫沉淀富集得到的DNA构建为标准Illumina ChIP-Seq文库并完成测序。