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Cpeb1b-mediated cytoplasmic polyadenylation of shha mRNA modulates zebrafish definitive hematopoiesis

ABSTRACT: During vertebrate embryogenesis, hematopoietic stem and progenitor cell (HSPC) production through endothelial-to-hematopoietic transition requires suitable developmental signals, but how these signals are accurately regulated remains incompletely understood. Cytoplasmic polyadenylation, which is one of the posttranscriptional regulations, plays a crucial role in RNA metabolism. Here, we report that Cpeb1b-mediated cytoplasmic polyadenylation is important for HSPC specification by translational control of Hedgehog (Hh) signaling during zebrafish early development. Cpeb1b is highly expressed in notochord and its deficiency results in defective HSPC production. Mechanistically, Cpeb1b regulates hemogenic endothelium specification by the Hedgehog–Vegf–Notch axis. We demonstrate that the cytoplasmic polyadenylation element motif-dependent interaction between Cpeb1b and shha messenger RNA (mRNA) in the liquid-like condensates, which are induced by Pabpc1b phase separation, is required for cytoplasmic polyadenylation of shha mRNA. Intriguingly, the cytoplasmic polyadenylation regulates translation but not stability of shha mRNA, which further enhances the Shha protein level and Hh signal transduction. Taken together, our findings uncover the role of Cpeb1b-mediated cytoplasmic polyadenylation in HSPC development and provide insights into how posttranscriptional regulation can direct developmental signals with high fidelity to translate them into cell fate transition.

ORGANISM(S): Danio rerio

PROVIDER: GSE207906 | GEO | 2023/02/06

REPOSITORIES: GEO

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Project description:Misactivation of the Hedgehog (Hh) pathway can cause cancers such as medulloblastomas, the most common malignant brain tumor in children, and basal cell carcinomas, the most common cancer in the United States. Hedgehog signals are transmitted through primary cilia, where Hedgehog ligands bind to Patched1 and activate Smoothened through interactions with cilia-associated sterol lipids. The gene expression programs driving cellular responses to ciliary Hh signals are incompletely understood. Thus, to define Hh target genes, we performed RNA sequencing of cells after treatment with Hh ligands (Shh, Dhh, Ihh), cilia-associated lipids (7b,27-dihydroxycholesterol, 24(S),25-epoxycholesterol), or synthetic lipids or small molecules that activate Smoothened (20(S)-hydroxycholesterol, SAG). Treatment with Hh pathway agonists identified a core gene expression program comprised of 155 genes driving lipid synthesis, metabolism, signaling, adhesion, or angiogenesis. These datasets were integrated with RNA sequencing of Hh-human medulloblastomas (n=?), a Math1-Cre SmoM2 mouse genetic model of Hh-associated medulloblastoma (n=?), and human basal cell carcinomas (n=10) to ascertain how malignant Hh signaling differs from canonical Hh signaling. We discover a conserved response to ciliary Hh signals in human or mouse medulloblastomas, including known target genes such as Gli1 or Ptch1, and novel target genes such as Hsd11b1 or Retnla. Importantly, mechanistic studies reveal Hsd11b1 to be a putative negative regulator of Hh signaling that is dysregulated in malignancies. We further demonstrate Retnla to be a positive regulator of Hh signaling that drives expression of Hsd11b2, a druggable dependency underlying Hedgehog-associated medulloblastoma. Orthotopic implantation of neuroepithelial stem cells that overexpress either Hsd11b1 and Retnla demonstrate that tumors derived Hsd11ß1 overexpression are more primitive and less aggressive whereas Retnla overexpression forms tumors that are more differentiated and behave more aggressively. In sum, we illuminate the first comprehensive transcriptome of Hh signaling and highlight the intricate interplay between Hh signaling and lipid metabolism that Hh-dependent malignancies dysregulate to drive tumor progression.

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Cpeb1b-mediated cytoplasmic polyadenylation of shha mRNA modulates zebrafish definitive hematopoiesis

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