title: A monoallelic-to-biallelic T-cell transcriptional switch regulates GATA3 abundance.
abstract: Protein abundance must be precisely regulated throughout life, and nowhere is the stringency of this requirement more evident than during T-cell development: A twofold increase in the abundance of transcription factor GATA3 results in thymic lymphoma, while reduced GATA3 leads to diminished T-cell production. GATA3 haploinsufficiency also causes human HDR (hypoparathyroidism, deafness, and renal dysplasia) syndrome, often accompanied by immunodeficiency. Here we show that loss of one Gata3 allele leads to diminished expansion (and compromised development) of immature T cells as well as aberrant induction of myeloid transcription factor PU.1. This effect is at least in part mediated transcriptionally: We discovered that Gata3 is monoallelically expressed in a parent of origin-independent manner in hematopoietic stem cells and early T-cell progenitors. Curiously, half of the developing cells switch to biallelic Gata3 transcription abruptly at midthymopoiesis. We show that the monoallelic-to-biallelic transcriptional switch is stably maintained and therefore is not a stochastic phenomenon. This unique mechanism, if adopted by other regulatory genes, may provide new biological insights into the rather prevalent phenomenon of monoallelic expression of autosomal genes as well as into the variably penetrant pathophysiological spectrum of phenotypes observed in many human syndromes that are due to haploinsufficiency of the affected gene.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Ku
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
authors.forename: Kim-Chew
authors.initials: KC
authors.lastname: Lim
authors.affiliation: Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
authors.forename: Sundeep
authors.initials: S
authors.lastname: Kalantry
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; Life Sciences Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
authors.forename: James Douglas
authors.initials: JD
authors.lastname: Engel
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hosoya
mesh_terms: D000483:Alleles; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D050990:GATA3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D050990:GATA3 Transcription Factor; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1
keywords: GATA3; T-cell development; biallelic transcription; monoallelic transcription