The master regulator protein BAZ2B can reprogram human hematopoietic lineage-committed progenitors into a multipotent state
Bi-species, fusion-mediated, somatic cell reprogramming allows precise, organism-specific tracking of unknown lineage drivers. The fusion of Tcf7l1-/- murine embryonic stem cells with EBV-transformed human B cell lymphocytes, leads to the generation of bi-species heterokaryons. Human mRNA transcript profiling at multiple time points permits the tracking of the reprogramming of B cell nuclei to a multipotent state. Interrogation of a human B cell regulatory network with gene expression signatures identifies 8 candidate master regulator proteins. Of these 8 candidates, ectopic expression of BAZ2B, from the bromodomain family, efficiently reprograms hematopoietic committed progenitors into a multipotent state and significantly enhances their long-term clonogenicity, stemness, and engraftment in immunocompromised mice. Unbiased systems biology approaches let us identify the early driving events of human B cell reprogramming. ; This work was supported by Human Frontier Science Program Grant 2010 (to M.P.C. and A.C.); the European Union's Horizon 2020 Research and Innovation Programme (CellViewer no. 686637 to M.P.C); Ministerio de Ciencia e Innovación grant no. BFU2017-86760-P (AEI/FEDER, UE); AGAUR grant from Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement de la Generalitat de Catalunya ( 2017 SGR 689 to M.P.C.); Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology ( 20200730009 to M.P.C.); Juan de la Cierva Fellowship (to K.A.); BIST Master Fellowship (to X.T.); and the R35CA197745 outstanding NCI investigator award to A.C. We acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa , and the CERCA Programme (to M.P.C.), and the two instrumentation grants S10OD012351 and S10OD021764 to A.C. supporting the analytical work