DOI 10.1007/s00439-013-1413-1 RevIew PaPeR The grammar of transcriptional regulation

geometry as another dimension of combinatorial power for regulating transcription. Understanding the fundamen-tal principles governing transcriptional regulation could allow us to predict expression from DNa sequence, with far-reaching implications. Most notably, in many human diseases, genetic changes occur in non-coding regions such as gene promoters and enhancers. However, without under-standing the grammar of transcriptional regulation, we cannot tell which sequence changes affect expression and how. For example, even for a single binding site, we do not know the quantitative effects on expression of its location, orientation, and affinity; whether these effects are general, factor-specific, and/or promoter-dependent; and how they depend on the intrinsic nucleosome organization. Similarly, we do not know which properties determine whether mul