title: Hmga1 is differentially expressed and mediates silencing of the CD4/CD8 loci in T cell lineages and leukemic cells.
abstract: High-mobility group A1 (Hmga1) protein is an architectural chromatin factor, and aberrant Hmga1 expression in mice causes hematopoietic malignancies with defects in cellular differentiation. However, the functional involvement of Hmga1 in hematopoietic development and leukemic cells remains to be elucidated. Using Hmga1-green fluorescent protein (GFP) knock-in mice that endogenously express an Hmga1-GFP fusion protein, we examined Hmga1 expression in undifferentiated and differentiated populations of hematopoietic cells. During early T cell development in the thymus, Hmga1 is highly expressed in CD4/CD8-double negative (DN) cells and is transiently downregulated in CD4/CD8-double positive (DP) cells. Consistently, Hmga1 directly binds to cis-regulatory elements in the CD4/CD8 loci and the heterochromatin foci in DN-stage cells, but not in DP cells. Interestingly, CD4/CD8 expression in DN-stage leukemic cells is induced by inhibition of Hmga1 binding to nuclear DNA or RNA interference-mediated Hmga1 knockdown. In addition, Hmga1-depleted leukemic T cells markedly diminish proliferation, with transcriptional activation of cyclin-dependent kinase inhibitor genes as a direct target of Hmga1. The data in the present study reveal a role of Hmga1 in transcriptional silencing in T cell lineages and leukemic cells.
authors: Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, and Global Center of Excellence Cell Fate Regulation Research and Education Unit, Kumamoto University, Kumamoto, Japan.
authors: Yang
authors: Y
authors: Xi
authors: Sugiko
authors: S
authors: Watanabe
authors: Yuko
authors: Y
authors: Hino
authors: Chiyomi
authors: C
authors: Sakamoto
authors: Yuko
authors: Y
authors: Nakatsu
authors: Seiji
authors: S
authors: Okada
authors: Mitsuyoshi
authors: M
authors: Nakao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000235:genetics; D016827:CD8 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D055879:Gene Knock-In Techniques; D020868:Gene Silencing; D025741:HMGA1a Protein / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D025741:HMGA1a Protein