Building multifunctionality into a complex containing master regulators of hematopoiesis

Developmental controlmechanisms often use multimericcomplexes containing transcription factors, coregulators, and additional non-DNA binding components. It is challenging to ascertain how such components contribute to complex function at endogenous loci.We analyzed the function of components of a complex containing master regulators of hematopoiesis (GATA-1 and Scl/TAL1) and the non-DNA binding components ETO2, the LIM domain protein LMO2, and the chromatin looping factor LDB1. Surprisingly, we discovered that ETO2 and LMO2 regulate distinct target-gene ensembles in erythroid cells. ETO2 commonly repressed GATA-1 function via suppressing histone H3 acetylation, although it also regulated methylation of histone H3 at lysine 27 at select loci. Prior studies defined multiple modes by which GATA-1 regulates target genes with or without the coregulator Friend of GATA-1 (FOG-1). LMO2 selectively repressed genes that GATA-1 represses in a FOG-1-independent manner. As LMO2 controls hematopoiesis, its dysregulation is leukemogenic, and its influence on GATA factor function is unknown, this mechanistic link has important biological and pathophysiological implications. The demonstration that ETO2 and LMO2 exert qualitatively distinct functions at endogenous loci illustrates how components of complexes containing master developmental regulators can impart the capacity to regulate unique cohorts of target genes, thereby diversifying complex function.