Distinct roles for TET family proteins in regulating human erythropoiesis

Abstract

The ten-eleven translocation (TET) family of proteins plays important roles in a wide range of biological processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxy-methylcytosine. However, their function in erythropoiesis has remained unclear. We show here that TET2 and TET3 but not TET1 are expressed in human erythroid cells, and we explore the role of these proteins in erythropoiesis. Knockdown experiments revealed that TET2 and TET3 have different functions. Suppression of TET3 expression in human CD34 cells markedly impaired terminal erythroid differentiation, as reflected by increased apoptosis, the generation of bi/multinucleated polychromatic/orthochromatic erythroblasts, and impaired enucleation, although without effect on erythroid progenitors. In marked contrast, TET2 knockdown led to hyper-proliferation and impaired differentiation of erythroid progenitors. Surprisingly, knockdown of neither TET2 nor TET3 affected global levels of 5mC. Thus, our findings have identified distinct roles for TET2 and TET3 in human erythropoiesis, and provide new insights into their role in regulating human erythroid differentiation at distinct stages of development. Moreover, because knockdown of TET2 recapitulates certain features of erythroid development defects characteristic of myelodysplastic syndromes (MDSs), and the TET2 gene mutation is one of the most common mutations in MDS, our findings may be relevant for improved understanding of dyserythropoiesis of MDS.

5-Hydroxymethylcytosine (5hmC), or How to Identify Your Favorite Cell

“…This is the case for Tet2 (and to a lesser degree Tet3), which is consistently reported in murine models [39,40,43,[45][46][47]49] and human cells [37,38,42,[50][51][52]. Of note, the role of Tet2 in mast cell differentiation described above [40] is partially independent of 5hmC, as rescuing mast cell developmental changes upon Tet2 knockout was only possible by the re-expression of Tet2 independently of its catalytic activity, which assumes that Tet2 possibly interacts with other complexes (something similar has been shown between TET1 and the SIN3A co-repressor complex [53]).…”

TET2 is upregulated during erythroid differentiation of CD34+ cells from healthy donors and myelodysplastic syndrome patients

“…Pronier et al [8] demonstrated that the TET2 silencing increased granulomonocytic differentiation in detriment of erythroid differentiation in normal CD34 + cells. Yan et al [9], similarly demonstrated that TET2 inhibition led to MDS-like dyserythropoiesis. Of note, TET2 deletion leads to erythroid dysplasia and anemia in zebrafish model [14], suggesting a conserved function for TET2 in erythrocytes production.…”

“…Despite extensive studies, the specific contribution of TET2 in disease phenotype of myeloid neoplasms is not fully elucidated. Recent findings have brought attention to the role of TET2 in normal and malignant erythropoiesis [8,9].…”

Integrative proteomics reveals principles of dynamic phospho-signaling networks in human erythropoiesis

“…The resulting five populations/stages are henceforth colorcoded as follows: progenitors (mostly CFU-E) (Hu et al, 2013;Li et al, 2014a;Yan et al, 2017), yellow; ProE/EBaso, blue; LBaso day7, light pink; LBaso day14, dark pink; Poly, dark blue, and Ortho, orange ( Figure 1A-B).…”