An Erg-driven transcriptional program controls B cell lymphopoiesis

Abstract

B lymphoid development is initiated by the differentiation of hematopoietic stem cells into lineage committed progenitors, ultimately generating mature B cells. This highly regulated process generates clonal immunological diversity via recombination of immunoglobulin V, D and J gene segments. While several transcription factors that control B cell development and V(D)J recombination have been defined, how these processes are initiated and coordinated into a precise regulatory network remains poorly understood. Here, we show that the transcription factor ETS Related Gene (Erg) is essential for early B lymphoid differentiation. Erg initiates a transcriptional network involving the B cell lineage defining genes, Ebf1 and Pax5, which directly promotes expression of key genes involved in V(D)J recombination and formation of the B cell receptor. Complementation of Erg deficiency with a productively rearranged immunoglobulin gene rescued B lineage development, demonstrating that Erg is an essential and stage-specific regulator of the gene regulatory network controlling B lymphopoiesis.

Ontogenic shifts in cellular fate are linked to proteotype changes in lineage-biased hematopoietic progenitor cells

“…We found differential expression of known regulators of hematopoiesis (Arid3a, Erg, Nfkb1, Etv6, and Irf8), as well as several TFs with yet poorly described or undefined functions in early blood cell development (Aatf, Cebpz, Mybbp1a, Btf3, and Pura; Figures 2H and S2A). In addition to confirming the requirement of Erg in adult B lymphopoiesis (Loughran et al, 2008;Ng et al, 2011Ng et al, , 2020, the expression profile of this TF excludes it as a major driver of fetal lymphopoiesis (Figure S2A). Intriguingly, Btf3a TF with no defined role in hematopoiesis-followed the same expression pattern as the known fetal-enriched TF Arid3a (Zhou et al, 2015) (Figure 2H), highlighting its potential role as a regulator of fetal-specific features of hematopoiesis.…”

Single-cell epigenomic landscape of peripheral immune cells reveals establishment of trained immunity in individuals convalescing from COVID-19

“…5a) [30][31][32][33][34] -suggesting that the integrated B-cell lineage trajectory was a well-defined developmental programme that could be used to compare regulatory mechanisms between the healthy donors and individuals convalescing from COVID-19. Next, through integrated chromVAR TF deviations with similarly dynamic gene scores across differentiation states, we identified positive TF regulators with sequential activities of BCL11A, IRF8, PAX5, REL, BATF, IRF4, EBF1, POU2F2, TBET and LEF1 that promote B-cell commitment, differentiation, maintenance and class-switch recombination 30,[35][36][37][38][39] , thus resolving the integrated timing of TF activity for comparison (Fig. 4f and Extended Data Fig.…”

Regeneration of humoral immunity from pluripotent stem cells by defined transcription factors

“…In this study, we identify that synergistic expression of Runx1, Hoxa9 , and Lhx2 dominantly confers B cell lineage fate on PSC-derived iHPCs and leads to complete B lymphopoiesis in vivo following a differentiation scheme we previously reported (Guo et al, 2020; Wang et al, 2020). The regenerative B (iB) cells, including B-1a, B-1b, FO B, and MZ B subsets, possess a diversity of BCR repertoires similar to their natural B cell counterparts.…”