Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel, Annika; Schulte, Johannes H.; Weber, Susanne N.; Necke, Mandy; Händschke, Kathrin; Thor, Theresa; Pajtler, Kristian W.; Schramm, Alexander; König, Katharina; Diehl, Linda; Mestdagh, Pieter; Vandesompele, Jo; Speleman, Franki; Jastrow, Holger; Heukamp, Lukas C.; Schüle, Roland; Dührsen, Ulrich; Buettner, Reinhard; Eggert, Angelika; Göthert, Joachim R.

doi:10.1038/leu.2012.157

Cited by 179 publications

(177 citation statements)

References 46 publications

(90 reference statements)

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“…Hematopoieticselective loss of LSD1 also leads to profound decrease in total number of white blood cells (WBCs; Fig. S4B), consistent with a role for LSD1 in terminal differentiation of other hematopoietic lineages (15).…”

Section: Depletion Of Lsd1 Induces Hbf Expression and Impairs Erythromentioning

confidence: 76%

“…LSD1 homozygous KO mice are embryonic lethal with severe anemia. Deletion of LSD1 in adult bone marrow results in impaired function of hematopoietic stem cells, neutropenia, and markedly reduced number of leukocytes (15), indicating that LSD1 is necessary for specification and terminal differentiation of several hematopoietic lineages. Similarly, interference with LSD1 by shRNAs or inhibitors impairs erythroid maturation from human CD34 + HSPCs ex vivo (Figs.…”

Section: Discussionmentioning

confidence: 99%

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Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Bauer

Kerényi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

202

188

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Reactivation of fetal hemoglobin (HbF) in adults ameliorates the severity of the common β-globin disorders. The transcription factor BCL11A is a critical modulator of hemoglobin switching and HbF silencing, yet the molecular mechanism through which BCL11A coordinates the developmental switch is incompletely understood. Particularly, the identities of BCL11A cooperating protein complexes and their roles in HbF expression and erythroid development remain largely unknown. Here we determine the interacting partner proteins of BCL11A in erythroid cells by a proteomic screen. BCL11A is found within multiprotein complexes consisting of erythroid transcription factors, transcriptional corepressors, and chromatinmodifying enzymes. We show that the lysine-specific demethylase 1 and repressor element-1 silencing transcription factor corepressor 1 (LSD1/CoREST) histone demethylase complex interacts with BCL11A and is required for full developmental silencing of mouse embryonic β-like globin genes and human γ-globin genes in adult erythroid cells in vivo. In addition, LSD1 is essential for normal erythroid development. Furthermore, the DNA methyltransferase 1 (DNMT1) is identified as a BCL11A-associated protein in the proteomic screen. DNMT1 is required to maintain HbF silencing in primary human adult erythroid cells. DNMT1 haploinsufficiency combined with BCL11A deficiency further enhances γ-globin expression in adult animals. Our findings provide important insights into the mechanistic roles of BCL11A in HbF silencing and clues for therapeutic targeting of BCL11A in β-hemoglobinopathies.gene regulation | globin switching | hematopoiesis

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Section: Depletion Of Lsd1 Induces Hbf Expression and Impairs Erythromentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Bauer

Kerényi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

202

188

View full text Add to dashboard Cite

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“…By interacting with TAL1, the TAL1⅐LSD1⅐HDAC1 complex appears to control the onset of erythroid differentiation programs (22). Two recent in vivo studies further addressed that LSD1 plays a critical role in inhibiting HSPC gene expression programs and restraining progenitor proliferation, and LSD1 deficiency resulted in severe granulocytic and erythroid differentiation (20,21). We report that reduction of LSD1 stimulated the HSPC subpopulation from cultured bone marrows cells and preserved their primitive cell phenotypes (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…Interestingly, LSD1 also appears to act as a central regulator for HSPC proliferation and differentiation. In a conditional gene knockdown model, LSD1 reduction was found to expand BM progenitor numbers by enhancing their proliferative behavior (20). Additionally, knockout of LSD1 resulted in derepression of stem and progenitor cell gene signatures along with impaired granulocytic and erythroid maturation (21).…”

mentioning

confidence: 99%

Histone Lysine-specific Demethylase 1 (LSD1) Protein Is Involved in Sal-like Protein 4 (SALL4)-mediated Transcriptional Repression in Hematopoietic Stem Cells

Liu¹,

Souto

Liao

et al. 2013

Journal of Biological Chemistry

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Background: SALL4 plays important roles in regulating the growth of hematopoietic progenitor cells. Results: SALL4 dynamically recruits histone demethylase LSD1 to specific target genes. LSD1 negatively regulates SALL4-mediated gene expression by affecting local chromatin structure. Conclusion: Multiple epigenetic modifiers cooperatively modulate SALL4-mediated gene repression. Significance: This report provides a novel mechanism by which stem cell gene SALL4 controls hematopoietic progenitor cell properties.

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“…In addition, the contribution of LSD1 in leukemogenesis has been demonstrated, and the use of LSD1 inhibitors is being investigated as a new therapeutic strategy (49,50). The roles of LSD1 in hematopoiesis are various, and include the differentiation switch between erythropoiesis and myelopoiesis (44), the terminal differentiation of some hematopoietic lineages (47,48), maintenance of the undifferentiated state of plasma cells (46), globin switching (51)(52)(53), and the self-renewal of hematopoietic stem cells (48). Here, we unveiled new roles of LSD1, as a down-regulator of the endothelial characteristics and promoter of the hematopoietic commitment in hemangioblasts.…”

Section: Discussionmentioning

confidence: 99%

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

Takeuchi

Fuse

Watanabe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Cited by 179 publications

References 46 publications

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Corepressor-dependent silencing of fetal hemoglobin expression by BCL11A

Histone Lysine-specific Demethylase 1 (LSD1) Protein Is Involved in Sal-like Protein 4 (SALL4)-mediated Transcriptional Repression in Hematopoietic Stem Cells

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

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