GeneGround

Ground AI-generated omics interpretations against Claude Science evidence.

Across CRISPRi perturbations in primary human CD4+ T cells, several transcription factors show clear, reproducible perturbation-linked transcriptional responses that are consistent with their expected T cell biology. Knockdown of NFKB2 in 8-hour-stimulated cells produced a strong on-target reduction in NFKB2 expression (on-target effect size -32.6, significant at 10% FDR) and was associated with a broad response of 1,350 differentially expressed genes (761 up, 589 down). Genes upregulated after NFKB2 knockdown were enriched for an NF-kB / inflammatory signature and the Hallmark 'TNF-alpha signaling via NF-kB' gene set, consistent with altered NF-kB-associated transcriptional activity; this directional pattern was reproducible across four donors and both guides and recurred at 48 hours and, more weakly, at rest. This reproducible upregulation points to a regulatory role for NFKB2 in restraining the inflammatory program in stimulated cells. Knockdown of GATA3 (Stim8hr; on-target -20.0, 1,239 DE genes) was associated with coordinated downregulation of a Th2-polarization signature, including lower IL5, IL13, CCR8 and IL10, which is consistent with GATA3's established association with the Th2 program. In contrast, STAT1 knockdown (Stim8hr) produced a much smaller, more focused response (46 DE genes) in which downregulated genes were enriched for an interferon-response signature (e.g. GBP1, GBP4, IFITM3), consistent with reduced interferon-stimulated gene expression. A BATF knockdown result (Stim8hr) pointed in a similar activation-related direction but is reported here as exploratory because it rests on relatively few cells (135) with only 6 of 8 donor-guide pseudobulks passing quality control. Together, these knockdowns begin to define distinct arms of the CD4+ T cell response — inflammatory, Th2, and interferon. All of these are transcriptional associations from pseudobulk differential expression against non-targeting controls; CRISPRi represses rather than fully knocks out the target, and none of these results establishes a causal mechanism on its own.

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