Defective erythropoiesis in transgenic mice expressing dominant-negative upstream stimulatory factor

TY - JOUR

T1 - Defective erythropoiesis in transgenic mice expressing dominant-negative upstream stimulatory factor

AU - Liang, Shermi Y

AU - Moghimi, Babak

AU - Crusselle-Davis, Valerie J

AU - Lin, I-Ju

AU - Rosenberg, Michael H

AU - Li, Xingguo

AU - Strouboulis, John

AU - Huang, Suming

AU - Bungert, Jörg

PY - 2009/11

Y1 - 2009/11

N2 - Transcription factor USF is a ubiquitously expressed member of the helix-loop-helix family of proteins. It binds with high affinity to E-box elements and, through interaction with coactivators, aids in the formation of transcription complexes. Previous work demonstrated that USF regulates genes during erythroid differentiation, including HoxB4 and beta-globin. Here, we show that the erythroid cell-specific expression of a dominant-negative mutant of USF, A-USF, in transgenic mice reduces the expression of all beta-type globin genes and leads to the diminished association of RNA polymerase II with locus control region element HS2 and with the beta-globin gene promoter. We further show that the expression of A-USF reduces the expression of several key erythroid cell-specific transcription factors, including EKLF and Tal-1. We provide evidence demonstrating that USF interacts with known regulatory DNA elements in the EKLF and Tal-1 gene loci in erythroid cells. Furthermore, A-USF-expressing transgenic mice exhibit a defect in the formation of CD71(+) progenitor and Ter-119(+) mature erythroid cells. In summary, the data demonstrate that USF regulates globin gene expression indirectly by enhancing the expression of erythroid transcription factors and directly by mediating the recruitment of transcription complexes to the globin gene locus.

AB - Transcription factor USF is a ubiquitously expressed member of the helix-loop-helix family of proteins. It binds with high affinity to E-box elements and, through interaction with coactivators, aids in the formation of transcription complexes. Previous work demonstrated that USF regulates genes during erythroid differentiation, including HoxB4 and beta-globin. Here, we show that the erythroid cell-specific expression of a dominant-negative mutant of USF, A-USF, in transgenic mice reduces the expression of all beta-type globin genes and leads to the diminished association of RNA polymerase II with locus control region element HS2 and with the beta-globin gene promoter. We further show that the expression of A-USF reduces the expression of several key erythroid cell-specific transcription factors, including EKLF and Tal-1. We provide evidence demonstrating that USF interacts with known regulatory DNA elements in the EKLF and Tal-1 gene loci in erythroid cells. Furthermore, A-USF-expressing transgenic mice exhibit a defect in the formation of CD71(+) progenitor and Ter-119(+) mature erythroid cells. In summary, the data demonstrate that USF regulates globin gene expression indirectly by enhancing the expression of erythroid transcription factors and directly by mediating the recruitment of transcription complexes to the globin gene locus.

KW - Animals

KW - Antigens, CD/metabolism

KW - Chickens

KW - Chromatin Immunoprecipitation

KW - Embryo, Mammalian/embryology

KW - Embryonic Development/genetics

KW - Erythropoiesis/genetics

KW - Gene Expression Regulation, Developmental

KW - Genes, Dominant

KW - Mice

KW - Mice, Transgenic

KW - Models, Genetic

KW - Organ Specificity/genetics

KW - Promoter Regions, Genetic/genetics

KW - Protein Binding

KW - RNA Polymerase II/metabolism

KW - Receptors, Transferrin/metabolism

KW - Transcription Factors/genetics

KW - Upstream Stimulatory Factors/genetics

KW - beta-Globins/genetics

U2 - 10.1128/MCB.00419-09

DO - 10.1128/MCB.00419-09

M3 - Article

C2 - 19704006

SN - 0270-7306

VL - 29

SP - 5900

EP - 5910

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 21

ER -