Sp8regulatory function in the limb bud ectoderm

Abstract

Sp8 and Sp6 are two closely related Sp genes expressed in the limb ectoderm where they regulate proximo-distal and dorso-ventral patterning. Mouse genetics revealed that they act together in a dose-dependent manner but with Sp8 making a much greater contribution. Here, we combine ChIP-seq and RNA-seq genome-wide analyses to investigate the Sp8 regulatory network and mechanism of action. We find that Sp8 predominantly binds to putative distal enhancers to activate crucial limb patterning genes, including Fgf8, En1, Sp6 and Rspo2. Sp8 exerts its regulatory function by directly binding DNA at Sp consensus sequences or indirectly through Dlx5 interaction. Overall, our work underscores Sp8 master regulatory functions and supports a model in which it cooperates with other Dlx and Sp cofactors to regulate target genes. We believe that this model could help to properly understand the molecular basis of congenital malformations. Impact SentenceIn the limb ectoderm, Sp8 regulates master genes through a dual mechanism: directly binding DNA at Sp consensus sequences and indirectly engaging through Dlx5 interaction.

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“…Indeed, physical interactions were detected between Sp8 and Dlx5 and between Sp6 and Dlx5. However, the functional outcome of the interaction seems to be complex and likely depends on the availability of the interacting TFs [ 27 ]. Sp6 ChIP-seq analysis in developing mouse teeth similarly demonstrated that an AT-rich motif was enriched in the Sp6-bound genomic regions [ 28 ].…”

Regulatory landscape of Runx2 and Sp7 in osteoblast and chondrocyte lineages: Recent findings from next‐generation sequencer‐based studies

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