Jorge Ferrer and colleagues have mapped regulatory SNP variants associated in GWAS with type 2 diabetes risk and glycemic traits to large clusters of enhancer elements regulating the transcriptional identity of pancreatic β cells via a highly connected transcription factor network. Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.

The transcription start sites used during the maternal to zygotic transition in zebrafish are mapped, revealing that the transition is characterized by a switch between two different sequence signs to guide transcription initiation, which often co-exist in core promoters. The maternal-to-zygotic transition (MZT) during vertebrate embryogenesis represents a dramatic change of the transcriptome, when the zygotic genome is activated and maternal transcripts are degraded. This study maps the transcription start sites used during MZT in zebrafish at nucleotide resolution, and shows that the transition from maternal to zygotic transcriptome is characterized by a switch between two different promoter sequence signals. The position at which RNA transcription starts is determined by an A/T-rich motif at the maternal stage and by fundamentally different codes in the zygote. The two transcription start sites often coexist — and may even overlap — in core promoters and are differentially utilized at promoters active in both oocyte and embryo. A core promoter is a stretch of DNA surrounding the transcription start site (TSS) that integrates regulatory inputs1 and recruits general transcription factors to initiate transcription2. The nature and causative relationship of the DNA sequence and chromatin signals that govern the selection of most TSSs by RNA polymerase II remain unresolved. Maternal to zygotic transition represents the most marked change of the transcriptome repertoire in the vertebrate life cycle3,4,5,6. Early embryonic development in zebrafish is characterized by a series of transcriptionally silent cell cycles regulated by inherited maternal gene products: zygotic genome activation commences at the tenth cell cycle, marking the mid-blastula transition7. This transition provides a unique opportunity to study the rules of TSS selection and the hierarchy of events linking transcription initiation with key chromatin modifications. We analysed TSS usage during zebrafish early embryonic development at high resolution using cap analysis of gene expression8, and determined the positions of H3K4me3-marked promoter-associated nucleosomes9. Here we show that the transition from the maternal to zygotic transcriptome is characterized by a switch between two fundamentally different modes of defining transcription initiation, which drive the dynamic change of TSS usage and promoter shape. A maternal-specific TSS selection, which requires an A/T-rich (W-box) motif, is replaced with a zygotic TSS selection grammar characterized by broader patterns of dinucleotide enrichments, precisely aligned with the first downstream (+1) nucleosome. The developmental dynamics of the H3K4me3-marked nucleosomes reveal their DNA-sequence-associated positioning at promoters before zygotic transcription and subsequent transcription-independent adjustment to the final position downstream of the zygotic TSS. The two TSS-defining grammars coexist, often physically overlapping, in core promoters of constitutively expressed genes to enable their expression in the two regulatory environments. The dissection of overlapping core promoter determinants represents a framework for future studies of promoter structure and function across different regulatory contexts.