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Maternal IntS12 establishes a conserved Pol II checkpoint to safeguard selective zygotic genome activation

ABSTRACT: Early embryos must execute faithful zygotic genome activation (ZGA), rapidly initiating transcription while preventing indiscriminate output from thousands of RNA polymerase II (Pol II)–occupied promoters. Here, we identify maternal IntS12 as a conserved genome-wide “filter” that enforces the selectivity of ZGA. In Drosophila, loss of maternal IntS12 leads to widespread activation of pseudo-ZGA genes and disruption of transcriptional hierarchy. Mechanistically, IntS12 engages IntS1 through a highly constrained N-terminal helicase-containing element to selectively stabilize promoter-proximal pausing factors (NELF) at poised loci, thereby restricting premature pause release and limiting productive elongation. Strikingly, in mouse embryos, maternal INTS12 depletion similarly causes ZGA failure and early developmental arrest. A minimal ~33–amino acid containing-two helixes from INTS12 is sufficient for this activity, functioning as a compact and highly selective module that preserves pausing integrity while suppressing ectopic transcription. Together, our findings reveal that an evolutionarily conserved microdomain containing two helixes in IntS12 acts as a Pol II checkpoint to ensure robust and selective ZGA.

ORGANISM(S): Drosophila Melanogaster

SUBMITTER: Dahua Chen

PROVIDER: PXD080304 | iProX | Mon Jun 29 00:00:00 BST 2026

REPOSITORIES: iProX

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