Cis-trans divergence in the regulatory architectures of MYBL2 and MYB underlies distinct transcriptional networks in immunometabolic traits

초록

The MYB family genes encode transcription factors that orchestrate cellular proliferation, differentiation, and apoptosis; however, the regulatory architectures underlying their expression remain incompletely understood. Here, a genome-wide expression quantitative trait loci (eQTL) analysis of MYB family genes was conducted in a mixed-model framework using transcriptome and genotype data from lymphoblastoid cell lines (LCLs) of 373 European individuals. We identified 51 significant eQTLs (P<5 & times; 10(-)(8)), revealing a strikingly divergent regulatory architecture between MYB and MYBL2. Specifically, all 26 MYBL2-associated eQTLs were cis-acting, whereas MYB expression was regulated exclusively by 25 trans-eQTLs. These distinct cis- and trans-regulatory patterns were consistently replicated across multiple cohorts representing diverse ancestral backgrounds, supporting the robustness of the observed architecture. MYBL2 cis-eQTLs demonstrated broad cross-tissue reproducibility, including in immune- and metabolism-related tissues, highlighting the biological coherence and broad regulatory activity of MYBL2. Transcriptome-wide eGenes associated with MYB family eQTLs supported a ubiquitously acting regulatory profile for MYBL2, in contrast to a context-dependent regulatory role for MYB. Integrative downstream analyses incorporating genome-wide association study data, including Bayesian colocalization and Mendelian randomization, provided evidence that regulatory variants modulating MYB family gene expression contribute to immunometabolic traits. Collectively, these findings elucidate distinct cis-trans regulatory divergence of MYB family genes and a causal role of their regulatory variants in immunometabolic phenotypes. This work establishes a conceptual and analytical framework for future functional investigations aimed at elucidating the mechanisms by which MYB family genes and their regulatory architectures shape complex human traits.

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