Pioneer transcription factor TAL1 reshapes chromatin architecture to direct erythroid cell fate commitment [CUT&Tag]

Pioneer transcription factors critically regulate chromatin organization and hematopoietic cell lineage commitment. During erythropoiesis, hematopoietic stem cells undergo dynamic transcriptional and chromatin remodeling to differentiate into erythrocytes. Functionally validated pioneer factors capable of orchestrating erythropoiesis through dynamic chromatin remodeling remain limited, leaving their regulatory mechanisms incompletely resolved. Here, we identify T-cell acute lymphocytic leukemia 1(TAL1) as a pioneer factor that remodels chromatin to drive transcriptional reprogramming during erythropoiesis. By recruiting SWI/SNF complex, TAL1 drives erythroid fate specification while suppressing alternative lineages through lineage-restricted chromatin compartment reorganization. As a pioneer factor, TAL1 recruits chromatin remodelers BPTF and KMT2A to establish erythroid-specific genomic architecture. These complexes collectively execute TAL1 directed differentiation programs by transcriptionally activating erythroid regulators while repressing non-erythroid determinants. Our work establishes a generalizable chromatin accessibility-directed pioneer factor screening strategy, we identify TAL1 as a master pioneer factor and resolve its mechanism in driving erythroid commitment through 3D epigenome restructuring.