title: Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation.
abstract: Epigenetic alterations play a central role in the control of normal and malignant blood cell development. We demonstrate here that expression of a truncated DNA methyltransferase 3B isoform DNMT3B7, which has been shown to alter cellular epigenetic patterns, decreases the overall number of hematopoietic stem and progenitor cells (HSPCs), and markedly diminishes blood cell reconstitution within the female hormonal microenvironment. Gene expression profiling of HSPCs isolated from DNMT3B7 transgenic embryos identified Apolipoprotein E (Apoe) as overexpressed. The CpG island controlling Apoe expression had lower levels of modified cytosines in DNMT3B7 transgenic HSPCs, corresponding with the observed increase in gene expression. Furthermore, we observed that spleens and bone marrows of female mice transplanted with DNMT3B7 transgenic HSPCs express very high levels of Apoe. Finally, the introduction of Apoe-overexpressing HSPCs into male recipients decreased bone marrow engraftment, recapitulating our original observations in female recipients. Our work reveals a dynamic interplay between the intrinsic epigenetic changes in HSPCs and extrinsic endocrine factors acting on these cells to regulate the efficiency of HSPC engraftment and reconstitution. We have identified a novel mechanism by which gender-specific hormones modulate HSPC function, which could serve as a target for augmenting hematopoiesis in cases with limited HSC functionality.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Vasanthakumar
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Hayley
authors.initials: H
authors.lastname: Zullow
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Janet B
authors.initials: JB
authors.lastname: Lepore
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Kenya
authors.initials: K
authors.lastname: Thomas
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Young
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Reardon
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.|The University of Chicago Comprehensive Cancer Research Center, Chicago, Illinois, USA.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000096:biosynthesis* / Q000235:genetics; D018899:CpG Islands / Q000502:physiology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D006410:Hematopoiesis / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012727:Sex Characteristics
chemical_list: D001057:Apolipoproteins E; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: Apolipoprotein E; DNA methyltransferase 3B; Epigenetics; Gender-specific hormones; Hematopoiesis