Abstract
The five-membered SET and MYND domain-containing lysine methyltransferase (SMYD) family plays pivotal roles in development and differentiation. Initially characterized within the cardiovascular system, one such member, SMYD2, has been implicated in transcriptional and apoptotic regulation of hematopoiesis. Deletion of Smyd2 in adult mouse Hemaopoietic Stem Cells (HSC) using an interferon-inducible mx1-Cre-mediated conditional knockout (CKO) led to HSC reduction via both apoptosis and transcriptional deficiencies. Since HSC are specified from hemogenic endothelial (HE) cells in the dorsal aorta (DA), we sought to determine whether the flaw in HSC originated embryologically from this site. Toward this end, we performed deletion with vav-Cre mice, which is active in all hematopoietic and endothelial tissues from E10.5 embryonic life onward. Unexpectedly, we observed no defects in the embryo, other than apoptotic loss of definite HSC, whereas adult hematopoietic populations downstream were unaffected. These results further establish the importance of SMYD2 in antiapoptotic gene control of gene expression from the embryo to the adult.
Highlights
IntroductionSMYD2s role in cell proliferation [3,4,5] and a host of other proteins, further implicating its function in signal transduction pathways, hormone responses, and tumorigenesis [6,7,8,9,10]
Characterized in cardiomyocytes [1], the histone methyl transferase (HMTase) SMYD2 catalyzes monomethylation of histone H4 and dimethylation of histone H3, both associated with transcriptional repression [2], as well as methylating nonhistone proteins p53 and RB1 characterizingSMYD2s role in cell proliferation [3,4,5] and a host of other proteins, further implicating its function in signal transduction pathways, hormone responses, and tumorigenesis [6,7,8,9,10]
We have shown previously that mx1-Cre/Smyd2FloxFlox adults suffer defects in the emergence and/or maintenance of Hemaopoietic Stem Cells (HSC) [11]
Summary
SMYD2s role in cell proliferation [3,4,5] and a host of other proteins, further implicating its function in signal transduction pathways, hormone responses, and tumorigenesis [6,7,8,9,10]. Our prior findings demonstrated the importance of SMYD2 for proper lymphocyte development as well as the survival of hematopoietic leukemias [11]; little is known about the spatiotemporal expression or function of SMYD2 during embryogenesis. Members of the SMYD family are expressed prior to cellular differentiation during preimplantation development [12]; SMYD2 is expressed at the initial transition from the maternal to zygotic program at the 2–4 cell stage [13]. SMYD2 expression during embryo development was significantly enhanced during mesendodermal, Vet. Sci. SMYD2 activated transcription factors required for mesendodermal commitment via epigenetic promotion of H3 methylation near their corresponding transcriptional start sites [14]
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