Zbtb46 is a recently identified dendritic cell (DC)-specific transcription factor with poorly defined biology. Although Zbtb46 is highly expressed in conventional DCs, evidence also points to its presence in erythroid progenitors and endothelial cells suggesting that this factor might influence the early hematopoietic development. Here, we probe the effect of this transcription factor in embryonic stem cell (ESC)-derived blood cell progenitors using chemically inducible mouse cell lines. Unexpectedly, forced expression of this protein elicited a broad repressive effect at the early stage of ESC differentiation. Ectopic expression of Zbtb46 interfered with the mesoderm formation and cell proliferation was also negatively impacted. More importantly, reduced number of CD11b+ myeloid blood cells were generated from ESC-derived Flk1+ mesoderm cells in the presence of Zbtb46. Consistent with this finding, our gene expression profiling revealed that numerous myeloid and immune response related genes, including Irf8, exhibited lower expression in the Zbtb46-primed cells. Despite these repressive effects, however, Zbtb46 overexpression was associated with enhanced formation of erythroid blood cell colonies and increased adult hemoglobin (Hbb-b1) expression at the early phase of ESC differentiation. Moreover, elevated percent of CD105 (Endoglin) positive cells were detected in the Zbtb46-primed samples. In summary, our results support that Zbtb46 suppresses the ESC-derived myeloid development and diverts mesoderm cells toward erythroid developmental pathway. Moreover, our transcriptomic data provide a resource for exploration of the Zbtb46 regulatory network in ESC-derived progenitors.
Peripheral Myelin Protein 22 (PMP22) is mostly expressed in Schwann cells where it is essential in the compaction of myelin. The duplication of the PMP22 gene results in a hereditary demyelinating neuropathy of the Charcot-Marie-Tooth type 1A (CMT1A). So far there are only a few case reports suggesting that dysimmune mechanisms may take part in the pathophysiology of this disease. We describe three siblings carrying the duplication of the PMP22 gene, with a significant reduction of serum immunoglobulin G levels in all three cases and sural nerve vasculitis in the two women, which supports the proposition, that immune dysfunction may accompany this disease in some cases.
We have previously observed phenotypic and developmental changes upon the ectopic expression of the RUNX3 or the ZBTB46 transcription factors in mouse embryonic stem cell (ESC) derived progenitors. In this study we evaluated the gene expression profiles of the RUNX3- and the ZBTB46-instructed murine ESCs with RNA-Seq testing two next generation sequencing (NGS) technologies. We compared the DNA nanoball (DNB) based MGI DNBSEQ G400 sequencer with the bridge-PCR based Illumina NextSeq 500 instrument. Moreover, we also compared two types of MGI sequencing reagents (Standard- versus Hot-MPS) with the DNBSEQ G400. Importantly, very similar gene expression profile and greatly overlapping RUNX3 and ZBTB46 regulated gene sets were detected with both platforms. Moreover, almost identical gene expression pattern was obtained with the Hot-MPS reagent compared to the Standard-MPS chemistry. This transcriptomic analysis also facilitated the identification of RUNX3 and ZBTB46 regulated genes. For example, we found that Gzmd, Gdf6 and Ccr7 genes were robustly upregulated upon the forced expression of Runx3, on the other hand, Gpx2, Tdpoz4 and Arg2 were induced upon the ectopic expression of Zbtb46. Together these findings demonstrate that the DNBSEQ G400 system is also suitable for global transcript profiling and target gene selection with lower cost.
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