Multiple functions of Ldb1 required for beta-globin activation during erythroid differentiation.
Ldb1 and erythroid partners SCL, GATA-1, and LMO2 form a complex that is required to establish spatial proximity between the β-globin locus control region and gene and for transcription activation during erythroid differentiation. Here we show that Ldb1 controls gene expression at multiple levels. Ldb1 stabilizes its erythroid complex partners on β-globin chromatin, even though it is not one of the DNA-binding components. In addition, Ldb1 is necessary for enrichment of key transcriptional components in the locus, including P-TEFb, which phosphorylates Ser2 of the RNA polymerase C-terminal domain for efficient elongation. Furthermore, reduction of Ldb1 results in the inability of the locus to migrate away from the nuclear periphery, which is necessary to achieve robust transcription of β-globin in nuclear transcription factories. Ldb1 contributes these critical functions at both embryonic and adult stages of globin gene expression. These results implicate Ldb1 as a factor that facilitates nuclear relocation for transcription activation.
Song
Sang-Hyun
SH
Laboratory of Cellular and Developmental Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Kim
AeRi
A
Ragoczy
Tobias
T
Bender
M A
MA
Groudine
Mark
M
Dean
Ann
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D050982:GATA1 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D060588:LIM Domain Proteins; D019901:Locus Control Region; D008667:Metalloproteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D046912:Multiprotein Complexes; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D012319:RNA Polymerase II / Q000737:chemistry / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D055544:beta-Globins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D050982:GATA1 Transcription Factor; D060588:LIM Domain Proteins; D008667:Metalloproteins; D046912:Multiprotein Complexes; D042925:Positive Transcriptional Elongation Factor B; D011518:Proto-Oncogene Proteins; D012319:RNA Polymerase II; D012694:Serine; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D055544:beta-Globins; C494689:Gata1 protein, mouse; C102084:Ldb1 protein, mouse; C513188:Lmo2 protein, mouse; C489366:Tal1 protein, mouse