The Ets2 Repressor Factor (Erf) Is Required for Effective Primitive and Definitive Hematopoiesis

Peraki, Ioanna; Palis, James; Mavrothalassitis, George

doi:10.1128/mcb.00183-17

Cited by 14 publications

(17 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…ERF has recently been shown to be required for effective primitive and definitive hematopoiesis in mice. 37 Moreover, we noted that most of the eight CpG sites within the ERF promoter were hypermethylated in all three individuals in the HbF H group from WGBS data (Figure S2D). We subsequently validated this result with a bisulfite cloning method (Figure 1B), suggesting a possible association of ERF promoter hypermethylation with an elevated HbF level.…”

Section: Resultsmentioning

confidence: 83%

“…These findings are consistent with previous reports of impaired repopulation ability and quantitative differences in the differentiation of hematopoietic stem cells in the Erf-deficient mice. 37 We further noted that the variation of indel frequencies in the engrafted cells from edited mice were modest, 92% to 96% in BM cells and 85% to 90% in PB cells (Figure 3C), and that the indel frequencies in edited cells were consistent with that of input cells (88%), suggesting a high editing efficiency (Figure S7). Most importantly, in BM cells, we observed significant induction of g-globin in edited cells (mean of 22.4% of total b-like globin in edited cells compared with mean of 6.9% in unedited cells; Figure 3D).…”

Section: Validation Of Erf As An Hbf Repressor Via Engraftment Assays In Immunodeficient Micementioning

confidence: 76%

See 1 more Smart Citation

Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia

Bao

Zhang

Wang

et al. 2021

The American Journal of Human Genetics

View full text Add to dashboard Cite

The fetal-to-adult hemoglobin switch is regulated in a developmental stage-specific manner and reactivation of fetal hemoglobin (HbF) has therapeutic implications for treatment of b-thalassemia and sickle cell anemia, two major global health problems. Although significant progress has been made in our understanding of the molecular mechanism of the fetal-to-adult hemoglobin switch, the mechanism of epigenetic regulation of HbF silencing remains to be fully defined. Here, we performed whole-genome bisulfite sequencing and RNA sequencing analysis of the bone marrow-derived GYPA þ erythroid cells from b-thalassemia-affected individuals with widely varying levels of HbF groups (HbF R 95th percentile or HbF % 5th percentile) to screen epigenetic modulators of HbF and phenotypic diversity of b-thalassemia. We identified an ETS2 repressor factor encoded by ERF, whose promoter hypermethylation and mRNA downregulation are associated with high HbF levels in b-thalassemia. We further observed that hypermethylation of the ERF promoter mediated by enrichment of DNMT3A leads to demethylation of g-globin genes and attenuation of binding of ERF on the HBG promoter and eventually re-activation of HbF in b-thalassemia. We demonstrated that ERF depletion markedly increased HbF production in human CD34 þ erythroid progenitor cells, HUDEP-2 cell lines, and transplanted NCG-Kit-V831M mice. ERF represses g-globin expression by directly binding to two consensus motifs regulating g-globin gene expression. Importantly, ERF depletion did not affect maturation of erythroid cells. Identification of alterations in DNA methylation of ERF as a modulator of HbF synthesis opens up therapeutic targets for b-hemoglobinopathies.

show abstract

Section: Resultsmentioning

confidence: 83%

Section: Validation Of Erf As An Hbf Repressor Via Engraftment Assays In Immunodeficient Micementioning

confidence: 76%

Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia

Bao

Zhang

Wang

et al. 2021

The American Journal of Human Genetics

View full text Add to dashboard Cite

show abstract

“…32,33 Erf can induce erythroid differentiation, 34 whereas recently, it has been suggested that Erf is required for effective primitive and definitive hematopoiesis counteracting the function of other ETS family members. 35 In this study, we investigated the role of Erf in T lymphocytes maturation in the thymus and its effects in the peripheral T lymphocyte populations. To this end, we generated thymus-specific conditional knockout mice and evaluated how the elimination of Erf in the thymus affects the generation of conventional CD4SP and CD8SP and γδ thymocytes as well as the production of thymic and peripheral Tregs.…”

Section: Introductionmentioning

confidence: 99%

ETS2 repressor factor (ERF) is involved in T lymphocyte maturation acting as regulator of thymocyte lineage commitment

Tsiomita

Liveri

Vardaka

et al. 2022

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

Thymocyte differentiation and lineage commitment is regulated by an extensive network of transcription factors and signaling molecules among which Erk plays a central role. However, Erk effectors as well as the molecular mechanisms underlying this network are not well understood. Erf is a ubiquitously expressed transcriptional repressor regulated by Erk‐dependent phosphorylation. Here, we investigated the role of Erf in T cell maturation and lineage commitment, using a double‐fluorescent Erf‐floxed mouse to produce thymus‐specific Erf knockouts. We observed significant accumulation of thymocytes in the CD4/CD8 DP stage, followed by a significant reduction in CD4SP cells, a trend for lower CD8SP cell frequency, and an elevated percentage of γδ expressing thymocytes in Erf‐deficient mice. Also, an elevated number of CD69+TCRβ+ cells indicates that thymocytes undergoing positive selection accumulate at this stage. The expression of transcription factors Gata3, ThPOK, and Socs1 that promote CD4+ cell commitment was significantly decreased in Erf‐deficient mice. These findings suggest that Erf is involved in T cell maturation, acting as a positive regulator during CD4 and eventually CD8 lineage commitment, while negatively regulates the production of γδ T cells. In addition, Erf‐deficient mice displayed decreased percentages of CD4+ and CD8+ splenocytes and elevated levels of IL‐4 indicating that Erf may have an additional role in the homeostasis, differentiation, and immunologic response of helper and cytotoxic T cells in the periphery. Overall, our results show, for the first time, Erf's involvement in T cell biology suggesting that Erf acts as a potential regulator during thymocyte maturation and thymocyte lineage commitment, in γδ T cell generation, as well as in Th cell differentiation.

show abstract

“…ERF (ETS2 repressor factor) is a human ETS family transcription factor initially identified as a repressor of another ETS family factor, ETS2, as signified by its name . ERF is expressed ubiquitously in all cell types and found to play critical roles in hematopoiesis, , formation of placenta, , osteogenesis, and cranial development. , Mutations in ERF were shown to cause syndromic craniosynostosis, a severe skull deformity resulting in disruption of normal brain development. , …”

mentioning

confidence: 99%

Structural Insight into the DNA Binding Function of Transcription Factor ERF

et al. 2020

View full text Add to dashboard Cite

ETS family transcription factors control development of different cell types in humans, whereas deregulation of these proteins leads to severe developmental syndromes and cancers. One of a few members of the ETS family that are known to act solely as repressors, ERF, is required for normal osteogenesis and hematopoiesis. Another important function of ERF is acting as a tumor suppressor by antagonizing oncogenic fusions involving other ETS family factors. The structure of ERF and the DNA binding properties specific to this protein have not been elucidated. In this study, we determined two crystal structures of the complexes of the DNA binding domain of ERF with DNA. In one, ERF is in a distinct dimeric form, with Cys72 in a reduced state. In the other, two dimers of ERF are assembled into a tetramer that is additionally locked by two Cys72–Cys72 disulfide bonds across the dimers. In the tetramer, the ERF molecules are bound to a pseudocontinuous DNA on the same DNA face at two GGAA binding sites on opposite strands. Sedimentation velocity analysis showed that this tetrameric assembly forms on continuous DNA containing such tandem sites spaced by 7 bp. Our bioinformatic analysis of three previously reported sets of ERF binding loci across entire genomes showed that these loci were enriched in such 7 bp spaced tandem sites. Taken together, these results strongly suggest that the observed tetrameric assembly is a functional state of ERF in the human cell.

show abstract

The Ets2 Repressor Factor (Erf) Is Required for Effective Primitive and Definitive Hematopoiesis

Cited by 14 publications

References 54 publications

Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia

Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia

ETS2 repressor factor (ERF) is involved in T lymphocyte maturation acting as regulator of thymocyte lineage commitment

Structural Insight into the DNA Binding Function of Transcription Factor ERF

Contact Info

Product

Resources

About