title: Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells.
abstract: The stem cell protein SALL4 plays a critical role in hematopoiesis by regulating the cell fate. In primitive hematopoietic precursors, it activates or represses important genes via recruitment of various epigenetic factors such as DNA methyltransferases, and histone deacylases. Here, we demonstrate that LSD1, a histone lysine demethylase, also participates in the trans-repressive effects of SALL4. Based on luciferase assays, the amine oxidase domain of LSD1 is important in suppressing SALL4-mediated reporter transcription. In freshly isolated adult mouse bone marrows, both SALL4 and LSD1 proteins are preferentially expressed in undifferentiated progenitor cells and co-localize in the nuclei. Further sequential chromatin immunoprecipitation assay confirmed that these two factors share the same binding sites at the promoter regions of important hematopoietic regulatory genes including EBF1, GATA1, and TNF. In addition, studies from both gain- and loss-of-function models revealed that SALL4 dynamically controls the binding levels of LSD1, which is accompanied by a reversely changed histone 3 dimethylated lysine 4 at the same promoter regions. Finally, shRNA-mediated knockdown of LSD1 in hematopoietic precursor cells resulted in altered SALL4 downstream gene expression and increased cellular activity. Thus, our data revealed that histone demethylase LSD1 may negatively regulate SALL4-mediated transcription, and the dynamic regulation of SALL4-associated epigenetic factors cooperatively modulates early hematopoietic precursor proliferation.
authors.affiliation: From the Departments of Surgery.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Joseph
authors.initials: J
authors.lastname: Souto
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liao
authors.forename: Yongping
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yangqiu
authors.initials: Y
authors.lastname: Li
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishinakamura
authors.forename: Suming
authors.initials: S
authors.lastname: Huang
authors.forename: Todd
authors.initials: T
authors.lastname: Rosengart
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Schuster
authors.forename: Yupo
authors.initials: Y
authors.lastname: Ma
authors.forename: Jianchang
authors.initials: J
authors.lastname: Yang
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001665:Binding Sites; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D015254:DNA Modification Methylases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology; D056466:Histone Demethylases; D006657:Histones / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000235:genetics; D051379:Mice; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015254:DNA Modification Methylases; D004268:DNA-Binding Proteins; D056466:Histone Demethylases; D006657:Histones; D008239:Lysine; D010089:Oxidoreductases, N-Demethylating; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D014157:Transcription Factors; C509167:Sall4 protein, mouse; C067143:TAL1 protein, human; C504076:KDM1a protein, mouse
keywords: Bone Marrow; DNA Methylation; Hematopoiesis; Hematopoietic Progenitor; Histone Demethylation; Mi-2·NuRD Complex; Repressor Protein; SALL Family; Stem Cells