Data from: Nuclear microenvironments modulate transcription from low-affinity enhancers

Transcription factors bind low-affinity DNA sequences for only short durations. It is not clear how brief, low-affinity interactions can drive efficient transcription. Here we report that the transcription factor Ultrabithorax (Ubx) utilizes low-affinity binding sites in the Drosophila melanogaster shavenbaby (svb) locus and related enhancers in nuclear microenvironments of high Ubx concentrations. Related enhancers colocalize to the same microenvironments independently of their chromosomal location, suggesting that microenvironments are highly differentiated transcription domains. Manipulating the affinity of svb enhancers revealed an inverse relationship between enhancer affinity and Ubx concentration required for transcriptional activation. The Ubx cofactor, Homothorax (Hth), was co-enriched with Ubx near enhancers that require Hth, even though Ubx and Hth did not co-localize throughout the nucleus. Thus, microenvironments of high local transcription factor and cofactor concentrations could help low-affinity sites overcome their kinetic inefficiency. Mechanisms that generate these microenvironments could be a general feature of eukaryotic transcriptional regulation.

转录因子与低亲和力DNA序列的结合仅能维持较短时长。目前尚不明确这类短暂且低亲和力的相互作用如何驱动高效的转录过程。本研究表明，转录因子超胸节蛋白（Ultrabithorax, Ubx）可在自身浓度较高的核微环境中，靶向结合黑腹果蝇（Drosophila melanogaster）shavenbaby（svb）基因座及相关增强子内的低亲和力结合位点。相关增强子无需依赖自身染色体位置即可共定位至同一核微环境，这提示核微环境是高度特化的转录调控结构域。通过调控svb增强子的亲和力，研究人员发现增强子亲和力与转录激活所需的Ubx浓度之间呈负相关关系。Ubx的辅因子同源胸蛋白（Homothorax, Hth）会在依赖Hth的增强子附近与Ubx共同富集，尽管Ubx与Hth在全细胞核内并未发生共定位。由此可见，局部转录因子与辅因子浓度较高的核微环境，可帮助低亲和力结合位点克服其动力学低效性。构建这类核微环境的机制，可能是真核生物转录调控的一种普遍特征。