LSD1/KDM1A promotes hematopoietic commitment of hemangioblasts through downregulation of Etv2

Abstract

The hemangioblast is a progenitor cell with the capacity to give rise to both hematopoietic and endothelial progenitors. Currently, the regulatory mechanisms underlying hemangioblast formation are being elucidated, whereas those controllers for the selection of hematopoietic or endothelial fates still remain a mystery. To answer these questions, we screened for zebrafish mutants that have defects in the hemangioblast expression of Gata1, which is never expressed in endothelial progenitors. One of the isolated mutants, it627, showed not only down-regulation of hematopoietic genes but also up-regulation of endothelial genes. We identified the gene responsible for the it627 mutant as the zebrafish homolog of Lys-specific demethylase 1 (LSD1/KDM1A). Surprisingly, the hematopoietic defects in lsd1it627 embryos were rescued by the gene knockdown of the Ets variant 2 gene (etv2), an essential regulator for vasculogenesis. Our results suggest that the LSD1-dependent shutdown of Etv2 gene expression may be a significant event required for hemangioblasts to initiate hematopoietic differentiation.

Lsd1 interacts with cMyb to demethylate repressive histone marks and maintain inner ear progenitor identity

“…Therefore, by directly maintaining the expression of key players in the OEP module (Sox8, Pax2, Etv4 and Zbtb16) that precede its own expression, Lsd1 becomes part of a sub-network that acts like a central hub for the entire ear cascade. Interestingly, these Lsd1 targets are dependent on FGF signalling for their initial expression, and Lsd1 is known to regulate both Wnt and FGF signalling pathways (Chen et al, 2016;He et al, 2016;Huang et al, 2017Huang et al, , 2013Lei et al, 2015;Takeuchi et al, 2015).…”

“…In the zebrafish lateral line, Lsd1 is required to activate Etv4, Axin2 and Tcf7l2 to promote supporting cell proliferation upon hair cell damage (He et al, 2016), whereas it downregulates Etv2 to promote commitment of hematopoietic progenitor cells to their fate (Takeuchi et al, 2015). Furthermore, in cancer cells, Lsd1 promotes the Wnt pathway by repressing negative regulators of Wnt/β-catenin signalling such as APC, Prickle, Sfrp5 and Dkk1 (Huang et al, 2017(Huang et al, , 2013Lei et al, 2015).…”

“…Much of our understanding of the epigenetic regulation of cell fate decisions centres around maintenance of embryonic, neural or hematopoietic stem cells (Adamo et al, 2011;Foster et al, 2010;Sun et al, 2010;Takeuchi et al, 2015;Thambyrajah et al, 2016), cancer cells (Huang et al, 2017;Lei et al, 2015), and progenitor cell differentiation in the foetal or postnatal retina (Popova et al, 2016), anterior pituitary or nervous system (Ballas et al, 2005). In all these cases, Lsd1 acts as a co-repressor to either maintain stem cell identity or to allow differentiation towards a particular fate, mostly targeting H3K4me1 at enhancer or H3K4me2 at promoter regions.…”

SOX17 Regulates Conversion of Human Fibroblasts Into Endothelial Cells and Erythroblasts by Dedifferentiation Into CD34 + Progenitor Cells

“…Gene expression analysis by quantitative polymerase chain reaction showed expression of human hemoglobin beta and hemoglobin gamma, confirming the erythroid nature of the generated human cells (Figure 4F). The expression levels of hematopoietic transcriptional factors – RUNX1 and PU.1 , as well as the erythroblast transcription factor GATA1 , 24,25 were also markedly enhanced when compared with fibroblasts (Figure 4G). Moreover, erythroid colony-forming-cell assay demonstrated formation of distinct erythroid colonies (Figure 4H and 4I).…”

Lysine-specific histone demethylases in normal and malignant hematopoiesis

“…Further studies revealed an indispensable role for Kdm1a, in the context of Gfi-1/1b, for the emergence of HSCs from the AGM through silencing the endothelial program within the HE both in mice and zebrafish (13, 14), suggesting an evolutionary conserved role in definitive hematopoiesis. Conditional deletion of Kdm1a in fetal ( Vav1 Cre ) and adult ( Mx1 Cre ) HSPCs resulted in severe pancytopenia and compromised terminal differentiation of granulocytic and erythroid lineages (15, 16).…”