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Abstract

Developmental transcription factors act in networks, but how these
networks achieve cell- and tissue specificity is still poorly
understood. Here, we explored pre-B cell leukemia homeobox 1 (PBX1) in
adult neurogenesis combining genomic, transcriptomic, and proteomic
approaches. ChIP-seq analysis uncovered PBX1 binding to numerous genomic
sites. Integration of PBX1 ChIP-seq with ATAC-seq data predicted
interaction partners, which were subsequently validated by mass
spectrometry. Whole transcriptome spatial RNA analysis revealed shared
expression dynamics of Pbx1 and interacting factors. Among these were
class I bHLH proteins TCF3 and TCF4. RNA-seq following Pbx1, Tcf3 or
Tcf4 knockdown identified proliferation- and differentiation associated
genes as shared targets, while sphere formation assays following
knockdown argued for functional cooperativity of PBX1 and TCF3 in
progenitor cell proliferation. Notably, while physiological PBX1-TCF
interaction has not yet been described, chromosomal translocation
resulting in genomic TCF3::PBX1 fusion characterizes a subtype of acute
lymphoblastic leukemia. Introducing Pbx1 into Nalm6 cells, a pre-B cell
line expressing TCF3 but lacking PBX1, upregulated the leukemogenic
genes BLK and NOTCH3, arguing that functional PBX1-TCF cooperativity
likely extends to hematopoiesis. Our study hence uncovers a
transcriptional module orchestrating the balance between progenitor cell
proliferation and differentiation in adult neurogenesis with potential
implications for leukemia etiology.
Graphical Abstract