Abstract
Members of the PR/SET domain-containing (PRDM) family of zinc finger transcriptional regulators play diverse developmental roles. PRDM10 is a yet uncharacterized family member, and its function in vivo is unknown. Here, we report an essential requirement for PRDM10 in pre-implantation embryos and embryonic stem cells (mESCs), where loss of PRDM10 results in severe cell growth inhibition. Detailed genomic and biochemical analyses reveal that PRDM10 functions as a sequence-specific transcription factor. We identify Eif3b, which encodes a core component of the eukaryotic translation initiation factor 3 (eIF3) complex, as a key downstream target, and demonstrate that growth inhibition in PRDM10-deficient mESCs is in part mediated through EIF3B-dependent effects on global translation. Our work elucidates the molecular function of PRDM10 in maintaining global translation, establishes its essential role in early embryonic development and mESC homeostasis, and offers insights into the functional repertoire of PRDMs as well as the transcriptional mechanisms regulating translation.
Highlights
Members of the PR/SET domain-containing (PRDM) family of zinc finger transcriptional regulators play diverse developmental roles
Through direct transcriptional regulation of Eif3b, a key translation initiation factor, we show that PRDM10 plays a critical role in maintaining global translation essential for mouse embryonic stem cells (mESCs) survival
While Prdm10Δ/+ mice were viable and fertile with no gross morphological or behavioral abnormalities observed in daily husbandry, no Prdm10Δ/Δ live pups were recovered from heterozygous intercrosses
Summary
Members of the PR/SET domain-containing (PRDM) family of zinc finger transcriptional regulators play diverse developmental roles. Our work elucidates the molecular function of PRDM10 in maintaining global translation, establishes its essential role in early embryonic development and mESC homeostasis, and offers insights into the functional repertoire of PRDMs as well as the transcriptional mechanisms regulating translation. Prdm[1] is required for primordial germ cell specification and branchial arch patterning during embryonic development[4], and plays an important role in regulating hematopoietic lineage differentiation[5]. We establish a conditional Prdm[10] knockout mouse model to uncover a critical role for PRDM10 during very early embryonic development, and utilize mouse embryonic stem cells (mESCs) to study PRDM10’s biochemical and molecular properties. Through direct transcriptional regulation of Eif3b, a key translation initiation factor, we show that PRDM10 plays a critical role in maintaining global translation essential for mESC survival
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