Synthetic regulatory reconstitution reveals principles of mammalian Hox cluster regulation

Sudarshan Pinglay, Milica Bulajić, Dylan P. Rahe, Emily Huang, Ran Brosh, Nicholas E. Mamrak, Benjamin R. King, Sergei German, John A. Cadley, Lila Rieber, Nicole Easo, Timothée Lionnet, Shaun Mahony, Matthew T. Maurano, Liam J. Holt, Esteban O. Mazzoni, Jef D. Boeke

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Article numbereabk2820
Issue number6601
StatePublished - Jul 1 2022

ASJC Scopus subject areas

  • General


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