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雄激素和糖皮质激素受体通过受体特异性和共享的 DNA 结合位点直接调控不同的转录程序。

Androgen and glucocorticoid receptor direct distinct transcriptional programs by receptor-specific and shared DNA binding sites.

机构信息

Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany.

Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

出版信息

Nucleic Acids Res. 2021 Apr 19;49(7):3856-3875. doi: 10.1093/nar/gkab185.

Abstract

The glucocorticoid (GR) and androgen (AR) receptors execute unique functions in vivo, yet have nearly identical DNA binding specificities. To identify mechanisms that facilitate functional diversification among these transcription factor paralogs, we studied them in an equivalent cellular context. Analysis of chromatin and sequence suggest that divergent binding, and corresponding gene regulation, are driven by different abilities of AR and GR to interact with relatively inaccessible chromatin. Divergent genomic binding patterns can also be the result of subtle differences in DNA binding preference between AR and GR. Furthermore, the sequence composition of large regions (>10 kb) surrounding selectively occupied binding sites differs significantly, indicating a role for the sequence environment in guiding AR and GR to distinct binding sites. The comparison of binding sites that are shared shows that the specificity paradox can also be resolved by differences in the events that occur downstream of receptor binding. Specifically, shared binding sites display receptor-specific enhancer activity, cofactor recruitment and changes in histone modifications. Genomic deletion of shared binding sites demonstrates their contribution to directing receptor-specific gene regulation. Together, these data suggest that differences in genomic occupancy as well as divergence in the events that occur downstream of receptor binding direct functional diversification among transcription factor paralogs.

摘要

糖皮质激素(GR)和雄激素(AR)受体在体内执行独特的功能,但它们的 DNA 结合特异性几乎相同。为了确定促进这些转录因子同源物功能多样化的机制,我们在等效的细胞环境中对它们进行了研究。染色质和序列分析表明,不同的结合以及相应的基因调控,是由 AR 和 GR 与相对难以接近的染色质相互作用的不同能力驱动的。不同的基因组结合模式也可能是 AR 和 GR 之间 DNA 结合偏好的细微差异的结果。此外,选择性占据的结合位点周围的大片段(>10 kb)的序列组成差异很大,表明序列环境在引导 AR 和 GR 到不同的结合位点方面发挥作用。对共享结合位点的比较表明,通过受体结合下游发生的事件的差异也可以解决特异性悖论。具体来说,共享结合位点显示出受体特异性增强子活性、辅助因子募集和组蛋白修饰的变化。共享结合位点的基因组缺失证明了它们对指导受体特异性基因调控的贡献。总之,这些数据表明,基因组占据的差异以及受体结合下游发生的事件的差异指导转录因子同源物的功能多样化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cab0/8053126/1503c00f3214/gkab185fig1.jpg

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