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We mapped the causal control architecture of a human immune cell and used it to nominate druggable, disease-relevant targets.

Code Video Cerebral Valley

Core trick

Builds a directed causal network with one edge per validated knockdown-to-gene effect, then measures hub concentration with a Gini coefficient.

Tags

sciencehealth

Description

We mapped the causal control architecture of a human immune cell and used it to nominate druggable, disease-relevant targets. From the Marson-lab genome-scale CRISPRi Perturb-seq atlas (22M primary human CD4+ T cells; rest / 8h / 48h activation) we built the causal trans-regulatory network for every validated knockdown -> differentially-expressed gene is one edge, and characterised its architecture. Finding: the network is hub-dominated and sparse-but-pleiotropic (the top 5% of regulators drive ~78% of all trans-effects). The first causal confirmation of the Pritchard-lab 2026 topology prediction. Across activation, it is shape-invariant but identity-labile; the concentration (Gini ~ 0.92) is pinned across all states while up to 59% of the top hubs are replaced. The cell keeps the shape of its control while swapping out who is in control. Every result survives power, edge-definition, knockdown-efficiency and detectability confounds, and replicates in a different cell type (K562). Why it matters: the hubs that switch on specifically with activation are ~2x enriched for monogenic-disease genes and are druggable (ZAP70, ITK, LCK, PTPRC, IL12RB2). The candidate state-specific control points for immune modulation. All results are reproduced from public data with code, a streaming notebook, and figures on GitHub.
Sneakypeat/HumanCD4CoDEGNet★ 20 forksJupyter NotebookMITCreated Jul 9, 2026 · last push Jul 13, 2026

README excerpt

# HumanCD4CoDEGNet — a shape-invariant, identity-labile control architecture

**Claude Hackathon: Life Sciences** (Researcher Track), 7–13 July 2026.
📄 **Live poster:** https://sneakypeat.github.io/HumanCD4CoDEGNet/

**Finding.** The *causal* trans-regulatory network of primary human CD4⁺ T cells is **hub-dominated and
sparse-but-pleiotropic** in every activation state — the first causal confirmation of the
Barton/Pritchard (*Cell Genomics* 2026) topology prediction, which was made from twin-study heritability
with no perturbation data. The architecture is **shape-invariant but identity-labile**: hub-dominance is
pinned at **Gini ≈ 0.92** across Rest → 8 h → 48 h even as the network densifies +32 % and up to **59 %
of the top-100 hubs are displaced**, with the TCR signalosome switching on as the activation-state
broadcaster. *The cell keeps the shape of its control while swapping out who is in control.*

Data: Marson-lab genome-scale CRISPRi Perturb-seq, ~22 M primary human CD4⁺ T cells (Zhu, Dann et al.
2025, bioRxiv 10.64898/2025.12.23.696273).

## Result in one line

| view (per activation state) | Rest | Stim 8h | Stim 48h |
|---|---|---|---|
| out-degree Gini (hub-dominance) | **0.921** | **0.929** | **0.923** |
| top 5 % of regulators → share of all trans-edges | 77 % | 80 % | 78 % |
| median regulators per gene (of ~11.3k possible) | 47 | 66 | 50 |
| total trans-edges | 592k | 780k | 663k |
| top-100 hubs displaced vs Rest | — | 44 % | 59 % |

Shape (Gini) invariant; i

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