title: The stem cell zinc finger 1 (SZF1)/ZNF589 protein has a human-specific evolutionary nucleotide DNA change and acts as a regulator of cell viability in the hematopoietic system.
abstract: The stem cell zinc finger 1 (SZF1)/ZNF589 protein belongs to the large family of Krüppel-associated box domain-zinc finger (KRAB-ZNF) transcription factors, which are present only in higher vertebrates and epigenetically repress transcription by recruiting chromatin-modifying complexes to the promoter regions of their respective target genes. Although the distinct biological functions of most KRAB-ZNF proteins remain unknown, recent publications indicate their implication in fundamental processes, such as cell proliferation, apoptosis, differentiation, development, and tumorigenesis. SZF1/ZNF589 was first identified as a gene with SZF1-1 isoform specifically expressed in CD34(+) hematopoietic cells, strongly suggesting a role in epigenetic control of gene expression in hematopoietic stem/progenitor cells (HSPCs). However, the function of SZF1/ZNF589 in hematopoiesis has not yet been elucidated. Our study reveals SZF1/ZNF589 as a gene with a human-specific nucleotide DNA-change, conferring potential species-specific functional properties. Through shRNA-mediated loss-of-function experiments, we found that changes in expression of fundamental apoptosis-controlling genes are induced on SZF1/ZNF589 knockdown, resulting in inhibited growth of hematopoietic cell lines and decreased progenitor potential of primary human bone marrow CD34(+) cells. Moreover, we found that the SZF1/ZNF589 gene is differentially regulated during hypoxia in CD34(+) HSPCs in a cytokine-dependent manner, implicating its possible involvement in the maintenance of the hypoxic physiologic status of hematopoietic stem cells. Our results establish the role of SZF1/ZNF589 as a new functional regulator of the hematopoietic system.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany. Electronic address: venturini.letizia@mh-hannover.de.
authors.forename: Letizia
authors.initials: L
authors.lastname: Venturini
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stadler
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Georgi
authors.initials: G
authors.lastname: Manukjan
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Scherr
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schlegelberger
authors.affiliation: Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Steinemann
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics*; D018388:Codon, Terminator; D019143:Evolution, Molecular; D055785:Gene Knockdown Techniques; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D017354:Point Mutation; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D018388:Codon, Terminator; D012097:Repressor Proteins; C117566:ZNF589 protein, human