Regulation of hematopoietic development by ZBTB transcription factors

Abstract

Hematopoietic development is governed by the coordinated expression of lineage- and differentiation stage-specific genes. Transcription factors play major roles in this process and their perturbation may underlie hematologic and immunologic disorders. Nearly 1900 transcription factors are encoded in the human genome: of these, 49 BTB (for broad-complex, tram-track and bric à brac)-zinc finger transcription factors referred to as ZBTB or POK proteins have been identified. ZBTB proteins, including BCL6, PLZF, ThPOK and LRF, exhibit a broad spectrum of functions in normal and malignant hematopoiesis. This review summarizes developmental and molecular functions of ZBTB proteins relevant to hematology.

Keywords: Co-repressor; Hematopoiesis; Transcription factor.

Fig. 1

Structure and function of ZBTB protein domains. a The BTB domain serves as a protein/protein interaction module, while zinc fingers primarily function as a DNA binding module. The linker domain is unstructured and often targeted for posttranslational modification. The number of zinc finger motifs (ZF) varies among ZBTB proteins. Structures of the LRF-BTB domain and KAISO zinc fingers were obtained from PDB files 2NN and 4F6 N, respectively. b (i) Classical model of ZBTB/DNA interaction. Histone-binding modules of SMRT/NCOR (such as the SANT domain) or PHD domains of CHD3/4, subunits of the NuRD complex, could stabilize ZBTB/DNA binding in a chromatin context-dependent manner. (ii) A ZBTB dimer can bind DNA through one chain and interact with other proteins via the linker domain and/or zinc finger motifs. (iii) ZBTB protein may facilitate long-range interactions with regulatory regions (at promoters or enhancers)

Fig. 2

ZBTB proteins and lymphoid development. a Schematic view of T cell and innate lymphoid cell development in mice. ZBTB proteins necessary for development and/or maintenance are indicated. HSC hematopoietic stem cell, MPP multi-potential progenitor, LMPP lymphoid-biased MPP, CLP common lymphoid progenitor, ETP early T cell precursor, DN CD4/8 double-negative T, DP CD4/8 double-positive T, iNKT invariant natural killer T, Th1 T helper 1, Th2 T helper 2, Tfh follicular helper T, Treg regulatory T, Th17 T helper 17, CILP common innate lymphoid progenitor, ILC innate lymphoid cell. b Transcriptional regulation of genes necessary for CD4/8 T (top) or Tfh cell development (bottom). ZBTB proteins are depicted in red. c B cell development in mice. MIZ1 and ZBTB1 are necessary for early B cell development in BM, while LRF, BCL6 and ZBTB20 function in mature B cell compartments. Trans. B transitional B, MZB marginal zone B, FOB follicular B, Pre-GCB pre-germinal center B, GCB germinal center B, LL Plasma long-lived plasma cell. d Transcriptional regulation of genes necessary for GCB and plasma cell development

Fig. 3

ZBTB proteins and myeloid development. a Schematic view of myeloid development in BM. ZBTB proteins necessary for the development and/or function are indicated. GMP granulocyte-macrophage progenitor, Neutro neutrophil, Baso basophil, Eosino eosinophil, MDP macrophage dendritic cell (DC) progenitor, CDPs common DC progenitors, cDC classical DC, pDC plasmacytoid DC, Mono monocyte, Mφ macrophage, OCP osteoclast progenitor, OC osteoclast, MEP megakaryocyte erythroid progenitor, BFU-E burst forming unit erythroid, CFU-E colony forming unit erythroid, ProE proerythroblast, BasoE basophilic erythroblast, PolyE polychromatophilic erythroblast, OrthoE orthochromatophilic erythroblast, RBC red blood cell, MkP megakaryocyte progenitor, Mk megakaryocyte, Plt platelet. b Transcriptional cascade regulating γ-globin expression in erythroblasts