Transforming Growth Factor beta (TGF-{beta}) signaling helps orchestrate multiple organismal traits in animals by regulating target gene expression. However, how this pathway's transcriptional regulators, called Smads, control target gene expression to generate different traits is not well understood. Using the C. elegans system, we identified the master chromatin remodeler B-lymphocyte maturation protein-1 (BLMP-1, a Kruppel-like zinc finger protein homologous to human PRDM1/BLIMP1) as a partner in Smad-mediated gene expression regulation. Previous research showed BLMP-1/PRDM1 controls organismal traits that the C. elegans TGF-{beta} superfamily member DBL-1 also affects. We identified genetic interactions between the DBL-1 pathway and blmp-1 for these traits. While BLMP-1/PRDM1 and DBL-1 pathway signaling had an additive effect on body size, blmp-1 mutants were epistatic to DBL-1 pathway mutants for male tail development, hermaphrodite gonad development, brood size, lipid levels, movement, and survival traits. We showed DBL-1 signaling transcriptionally regulates blmp-1 expression. We also identified a physical interaction between the DBL-1 pathway Smads and BLMP-1/PRDM1 using yeast-two hybrid analyses. Using bioinformatics and qPCR analysis, we showed that Smads and BLMP-1/PRDM1 regulate expression of common downstream target genes. Our work identifies novel interactions between the DBL-1 signaling pathway and BLMP-1, two conserved major transcriptional regulators, that ultimately influence a spectrum of organismal traits. We propose a model whereby BLMP-1/PRDM1 regulates DBL-1 signaling by acting as a gatekeeper, remodeling the chromatin architecture to control the access of the Smad complex to target genes. Together, our results reveal a direct link between a TGF-{beta} signaling pathway and a PRDM1-family master transcription regulator and offer clues to how they interact to control larval and adult traits. Our work suggests a conserved mechanism of transcriptional control of developmental traits by the Smad-PRDM axis.
Lakdawala, M. F., Madhu, B., Shaji, S., Crook, M., Gumienny, T. L.
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