Pioneer factor FOXA1 defines GATA2- and AR-mediated transcriptional program in prostate cancer [gene expression]

AR is tightly regulated by many transcriptional cofactors, including key pioneer factor such as FOXA1 and GATA2. While FOXA1 was recently shown to be able to redistribute AR across the genome, how GATA2 regulates AR cistrome has not been carefully investigated. Here, we report that, unlike FOXA1, GATA2 is unable to reprogram AR, but instead it enhances AR program by inducing AR expression and augmenting AR co-occupancy, thereby acting as a pure AR coactivator, rather than a pioneer factor. On the other hand, AR co-occupancy enhances both GATA2 and FOXA1 binding on the chromatin, forming a positive feedback loop. Importantly, we found that FOXA1 is also capable of reprogramming GATA2 by recruiting GATA2 from GATA motif to FKHD-containing regions, being analogous to its pioneering effect on AR signaling. By contrast, GATA2 simply acts as a co-activator of FOXA1 with a lack of pioneering ability. genetic_modification_design

雄激素受体（Androgen Receptor, AR）的活性受到众多转录辅因子的严格调控，其中包括FOXA1与GATA2这类关键的先锋转录因子（pioneer factor）。尽管近期研究已证实FOXA1能够在全基因组范围内重分布AR，但GATA2如何调控AR结合组（AR cistrome）尚未得到细致探究。本研究发现，与FOXA1不同，GATA2无法对AR进行重编程；相反，它通过诱导AR的表达并增强AR的染色质共占据（co-occupancy），从而作为纯粹的AR共激活因子（coactivator）发挥功能，而非先锋转录因子。另一方面，AR的染色质共占据能够增强GATA2与FOXA1在染色质上的结合，形成正向反馈环路。值得注意的是，我们还发现FOXA1同样能够通过将GATA2从GATA基序（GATA motif）招募至含FKHD结构域的区域，从而重编程GATA2，这与其对AR信号通路的先锋调控效应类似。与之相反，GATA2仅能作为FOXA1的共激活因子，并不具备先锋调控能力。genetic_modification_design