The transcriptional architecture of early human hematopoiesis identifies multilevel control of lymphoid commitment

Abstract

Understanding how differentiation programs originate from within the gene expression landscape of hematopoietic stem cells (HSC) is crucial to develop new clinical therapies. We mapped the transcriptional dynamics underlying the first steps of commitment by tracking transcriptome changes in human HSC and eight early progenitor populations. Transcriptional programs are extensively shared, extend across lineage-potential boundaries, and are not strictly lineage-affiliated. Elements of stem, lymphoid and myeloid programs are retained in multi-lymphoid progenitors (MLP), reflecting a hybrid transcriptional state. Based on functional single cell analysis, BCL11A, SOX4 and TEAD1 governed transcriptional networks within MLPs, leading to B cell specification. Overall, we show that integrated transcriptome approaches can identify novel regulators of multipotency and uncover additional complexity in lymphoid commitment.

Dendritic cell fate is determined by BCL11A

“…So clearly in addition to an effect on LSK hematopoiesis in general, there is a selective effect on CDP to pDC lineage development. In support of this selective effect, recent functional analyses (46) have provided compelling evidence that although BCL11A is expressed broadly among human HSCs and multilymphoid progenitors (MLPs)-which exhibit hybrid transcriptional states resembling stem, myeloid, and lymphoid programs extending across lineage-specific boundaries-the phenotype of silencing BCL11A in single-cell MLPs is consistent precisely with the phenotype of mice deficient in Bcl11a in which there is no B-cell development. The authors concluded that Bcl11a directs MLP commitment exclusively to the B-cell lineage and does not have a pan-lymphoid effect (46).…”

The Sox4/Tcf7l1 axis promotes progression of BCR-ABL-positive acute lymphoblastic leukemia

“…By using In normal hematopoiesis, TCF7L1 is predominantly expressed in human hematopoietic stem cells and multipotent progenitors, but is undetectable in pro-B cells. 26 Our findings that Tcf7l1 is expressed in transformed pro-B cells and that the expression is controlled by Sox4 suggest that gene expression profiles in transformed pro-B cells recapitulate those in early precursors and that Sox4 may play an important role in the reprograming. In our study, both Sox4 and Tcf7l1 had a pro-proliferation function in p190 BCR-ABL-transformed pro-B cells, suggesting that Tcf7l1 executes the role of Sox4 in leukemic cell proliferation.…”

The microRNA-212/132 cluster regulates B cell development by targeting Sox4

“…These included genes such as Rag1, Sfrp1, Eif2ak2, Irf7, Mx1, and Rsad2. Importantly, we found enrichment in the expression of several miR-132 targets in miR-212/132 / B cells compared with WT B cells, including the transcription factor Sox4, a known regulator of B cell development (Laurenti et al, 2013;Sun et al, 2013;Mallampati et al, 2014).…”