Figure 4. Modular pleiotropy within protein complexes resolves C7orf26 as a member of the Integrator complex INTS10–13-14 module.

(A) STAGA and ATAC protein complexes share a histone acetyltransferase module. From cancer cell fitness data alone, Webster inferred separate functional effects of STAGA and ATAC depletion while decomposing the effect of knocking out shared subunits as a mixture of STAGA and ATAC depletion.

(B) The SWI/SNF family protein complexes consist of specialized subunits bound to the common enzymatic subunit SMARCA4. From cancer cell fitness data alone, Webster inferred separate functional effects of depleting each subcomplex while decomposing the effect of SMARCA4 knockout as affecting all three subcomplexes.

(C) The Integrator complex is a modular RNA endonuclease complex. From cancer cell fitness data alone, Webster learned three distinct functional effects involving Integrator complex componentry. Each of the three functions captured the specific effect of knocking out recently discovered structural modules of the complex. An unknown interactor, C7orf26, was approximated as a mixture of all three Integrator functions, with the strongest loaded function mapping to the INTS10–13-14 functional module.

(D) Schematic of two C7orf26 gene splice variants curated by the genotype-tissue expression (GTEx) portal.

(E) Immunoprecipitation (IP) of C7orf26-HA variants from 293T nuclear extracts, immunoblotted for INTS10–13-14 module subunits.

(F) Mass spectrometry of C7orf26-HA and C7orf26-V5 immunoprecipitations from 293T cells shows stoichiometric pull down of INTS10, 13, and 14 with the full-length C7orf26.

(G) 293T cells with CRISPR-Cas9 perturbation of C7orf26 display loss of INTS10 at the protein level.

(H) IP of endogenous C7orf26 from 293T cells with and without INTS10 knockout.

(I) Model figure—C7orf26 stabilizes INTS10, which assembles together with the INTS13–14 heterodimer to form the INTS10–13-14-C7orf26 module.