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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 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

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Synthetic genomic reconstitution reveals principles of mammalian Hox cluster regulation [Hi-C]

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

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Synthetic genomic reconstitution reveals principles of mammalian Hox cluster regulation

Project description:Synthetic genomic reconstitution reveals principles of mammalian Hox cluster regulation

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Synthetic genomic reconstitution reveals principles of mammalian Hox cluster regulation [Hi-C]

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

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

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Morphogen gradient reconstitution reveals Hedgehog pathway design principles.

Project description:In developing tissues, cells estimate their spatial position by sensing graded concentrations of diffusible signaling proteins called morphogens. Morphogen-sensing pathways exhibit diverse molecular architectures, whose roles in controlling patterning dynamics and precision have been unclear. In this work, combining cell-based in vitro gradient reconstitution, genetic rewiring, and mathematical modeling, we systematically analyzed the distinctive architectural features of the Sonic Hedgehog pathway. We found that the combination of double-negative regulatory logic and negative feedback through the PTCH receptor accelerates gradient formation and improves robustness to variation in the morphogen production rate compared with alternative designs. The ability to isolate morphogen patterning from concurrent developmental processes and to compare the patterning behaviors of alternative, rewired pathway architectures offers a powerful way to understand and engineer multicellular patterning.

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