Two independent transcription initiation codes overlap on vertebrate core promoters

Haberle, V., Li, N., Hadzhiev, Y., Plessy, C., Previti, C., Nepal, C., Gehrig, J., Dong, X., Akalin, A., Suzuki, A.M., van IJcken, W.F., Armant, O., Ferg, M., Strähle, U., Carninci, P., Müller, F., and Lenhard, B.
Nature   507(7492): 381-385 (Journal)
Registered Authors
Armant, Olivier, Ferg, Marco, Gehrig, Jochen, Hadzhiev, Yavor, Li, Nan, Müller, Ferenc, Plessy, Charles, Strähle, Uwe
MeSH Terms
  • Animals
  • Base Sequence
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • Female
  • Gene Expression Regulation, Developmental/genetics
  • Histones/metabolism
  • Methylation
  • Mothers
  • Nucleosomes/genetics
  • Promoter Regions, Genetic/genetics*
  • Transcription Initiation Site*
  • Transcription Initiation, Genetic
  • Transcriptome/genetics
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zygote/metabolism
24531765 Full text @ Nature

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.

Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes