Biphasic control of the B cell transcriptome by mTORC1 and GSK3

A central question in immune regulation is how cells coordinate transcriptional responses to environmental cues. It remains unclear whether transcriptional regulation is controlled by isolated mechanism or integrated regulatory programs. Here, we develop a high-sensitivity, genome-wide CRISPR-Cas9 screening platform with 47 transcriptional reporters in human B cell lymphoma, identifying 4,440 regulators and 17,638 regulatory interactions. To enable the exploration of these networks, we establish B-LEARN, an interactive portal for data visualization and discovery. Our results reveal a large number of shared regulators across our 47 screens that act as context-dependent activators or repressors. Globally, we uncover a biphasic regulatory architecture in which mTORC1 and GSK3 exert opposing control over the B cell transcriptome. Notably, mTOR inhibition broadly activates key B cell genes, an effect antagonized by GSK3. Thus, B cell transcription is governed by an integrated, pathway-driven circuit, offering new targets to modulate gene expression in lymphoma and autoimmune disease.