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Synthetic genomic reconstitution reveals principles of mammalian Hox cluster regulation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Rattus norvegicus

PROVIDER: GSE190906 | GEO | 2021/12/16

REPOSITORIES: GEO

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Synthetic regulatory reconstitution reveals principles of mammalian <i>Hox</i> cluster regulation.

Project description: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.

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Synthetic genomic reconstitution reveals principles of mammalian Hox cluster regulation [RNA-Seq]

Project description:Precise Hox gene expression is crucial for embryonic patterning. Local transcription factor binding and distal enhancer elements have emerged as the major regulatory modes controlling the initiation and maintenance of Hox gene expression. However, quantifying their relative contributions has remained elusive. Here, we introduce ‘synthetic regulatory reconstitution’, a novel conceptual framework for studying gene regulation and apply it to the mammalian HoxA cluster. To measure the HoxA intrinsic regulatory potential and distal enhancer contributions, we de novo synthesized and delivered variant rat HoxA clusters (130-170 kilobases each) to an ectopic location in the mouse genome. We find that a minimal HoxA cluster lacking distal enhancers induces the appropriate gene set and establishes distinct chromatin domains in response to patterning signals, while distal enhancers are required for full transcriptional output. These results suggest that the genomically compact Hox clusters contain all the information to decode patterning signals and maintain positional information

2021-12-16 | GSE190896 | GEO