GENE REGULATION Synthetic regulatory reconstitution reveals principles of mammalian Hox cluster regulation

Precise Hox gene expression is crucial for embryonic patterning. Intra-Hox transcription factor binding and distal enhancer elements have emerged as the major regulatory modules controlling Hox gene expression. However, quantifying their relative contributions has remained elusive. Here, we introduce synthetic regulatory reconstitution, a conceptual framework for studying gene regulation, and apply it to the HoxA cluster. We synthesized and delivered variant rat HoxA clusters (130 to 170 kilobases) to an ectopic location in the mouse genome. We found that a minimal HoxA cluster recapitulated correct patterns of chromatin remodeling and transcription in response to patterning signals, whereas the addition of distal enhancers was needed for full transcriptional output. Synthetic regulatory reconstitution could provide a generalizable strategy for deciphering the regulatory logic of gene expression in complex genomes.

Automated summary

Precise Hox gene expression is essential for embryonic patterning. This study utilizes synthetic regulatory reconstitution to study gene regulation and focuses on the HoxA cluster. The researchers synthesized and delivered variant rat HoxA clusters to an ectopic location in the mouse genome, and found that a minimal HoxA cluster could reproduce the correct patterns of chromatin remodeling and transcription in response to patterning signals, while the addition of distal enhancers was necessary for full transcriptional output.