Deciphering the Zbtb46-mediated Control of Hematopoietic Development

Review of “Zbtb46-dependent altered developmental program in embryonic stem cell-derived blood cell progenitors” from STEM CELLS by Stuart P. Atkinson

A range of studies has provided evidence for the expression of the transcription factor Zbtb46 as a marker distinguishing dendritic cells (antigen-presenting immune cells) from macrophages/monocytes [1-3]. While Zbtb46 regulates multiple immunological pathways, including dendritic cell maturation, researchers led by Istvan Szatmari (University of Debrecen, Hungary) sought to further explore the Zbtb46 function outside the dendritic cell compartment.

Specifically, Boto et al. evaluated how the expression of Zbtb46 in mouse embryonic stem cells (ESCs) may impact hematopoietic differentiation; excitingly, the findings of this new STEM CELLSstudy now suggest that Zbtb46 suppresses myeloid development and diverts mesoderm cells toward erythroid development [4].

Using chemically-inducible mouse ESCs, the authors discovered that the forced expression of Zbtb46 altered the differentiation of ESCs at early stages; specifically, Zbtb46 interfered with the formation of mesoderm and dendritic cell-like immune cells and negatively impacted cell proliferation. Furthermore, the presence of elevated levels of Zbtb46 reduced the number of myeloid blood cells generated from ESC-derived mesoderm cells. The authors linked these myeloid-specific alterations to specific gene expression alterations; specifically, Zbtb46 induced a reduction in the expression of myeloid and immune response-related genes such as CD14, CD11b, and the myeloid lineage determining transcription factor interferon regulatory factor 8 (IRF8).

Interestingly, Zbtb46 overexpression impacted the erythroid differentiation of ESCs oppositely - Zbtb46 overexpression during the early phases of ESC differentiation enhanced formation of erythroid blood cell differentiation, increased adult hemoglobin expression (suggesting that this factor specifically stimulates adult-like red blood cell development), and increased the proportion of erythroid progenitor cells.

Overall, the authors demonstrate how the ectopic expression of a single transcription factor, Zbtb46, can alter the differentiation of ESCs in vitro by inhibiting myeloid development and promoting erythroid development. Furthermore, they anticipate that other members of the Zbtb transcription factor family, alone or in combination, may have relevance to the differentiation of ESCs or cell lineage conversion attempts.

For more on Zbtb46 function and the mechanisms behind hematopoietic differentiation, stay tuned to the Stem Cells Portal!

References

1. Miller JC, Brown BD, Shay T, et al., Deciphering the transcriptional network of the dendritic cell lineage. Nature Immunology 2012;13:888-899.
2. Satpathy AT, Kc W, Albring JC, et al., Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages. Journal of Experimental Medicine 2012;209:1135-1152.
3. Meredith MM, Liu K, Darrasse-Jeze G, et al., Expression of the zinc finger transcription factor zDC (Zbtb46, Btbd4) defines the classical dendritic cell lineage. Journal of Experimental Medicine 2012;209:1153-1165.
4. Boto P, Gerzsenyi TB, Lengyel A, et al., Zbtb46-dependent altered developmental program in embryonic stem cell-derived blood cell progenitors. STEM CELLS 2021;39:1322-1334.