0 9 Silencing silencing NN 10 12 of of IN 13 18 human human JJ 19 24 fetal fetal JJ 25 31 globin globin NN 32 42 expression expression NN 43 45 is be VBZ 46 54 impaired impaired JJ 55 57 in in IN 58 61 the the DT 62 69 absence absence NN 70 72 of of IN 73 76 the the DT 77 82 adult adult JJ 83 94 beta-globin beta-globin NN 95 99 gene gene NN 100 109 activator activator NN 110 117 protein protein NN 118 122 EKLF eklf NN 122 123 . . . 125 131 Globin Globin NNP 132 137 genes gene NNS 138 141 are be VBP 142 149 subject subject JJ 150 152 to to TO 153 168 tissue-specific tissue-specific JJ 169 172 and and CC 173 186 developmental developmental JJ 187 201 stage-specific stage-specific JJ 202 212 regulation regulation NN 212 213 . . . 214 215 A a DT 216 222 switch switch NN 223 227 from from IN 228 233 human human JJ 234 239 fetal fetal JJ 240 241 ( ( ( 241 250 gamma)-to gamma)-to JJ 251 256 adult adult NN 257 258 ( ( ( 258 270 beta)-globin beta)-globin NN 271 281 expression expression NN 282 288 occurs occur VBZ 289 295 within within IN 296 305 erythroid erythroid JJ 306 315 precursor precursor NN 316 321 cells cell NNS 322 324 of of IN 325 328 the the DT 329 334 adult adult JJ 335 342 lineage lineage NN 342 343 . . . 344 354 Previously previously RB 355 357 we we PRP 358 361 and and CC 362 368 others other NNS 369 375 showed show VBD 376 378 by by IN 379 387 targeted target VBN 388 392 gene gene NN 393 403 disruption disruption NN 404 408 that that IN 409 412 the the DT 413 417 zinc zinc NN 418 424 finger finger NN 425 429 gene gene NN 429 430 , , , 431 440 erythroid erythroid JJ 441 453 Kruppel-like kruppel-like JJ 454 460 factor factor NN 461 462 ( ( ( 462 466 EKLF EKLF NNP 466 467 ) ) ) 467 468 , , , 469 471 is be VBZ 472 480 required require VBN 481 484 for for IN 485 495 expression expression NN 496 498 of of IN 499 502 the the DT 503 514 beta-globin beta-globin NN 515 519 gene gene NN 520 522 in in IN 523 527 mice mouse NNS 527 528 , , , 529 539 presumably presumably RB 540 547 through through IN 548 559 interaction interaction NN 560 564 with with IN 565 566 a a DT 567 580 high-affinity high-affinity JJ 581 588 binding bind VBG 589 593 site site NN 594 596 in in IN 597 600 the the DT 601 609 proximal proximal JJ 610 618 promoter promoter NN 618 619 . . . 620 622 To to TO 623 630 examine examine VB 631 634 the the DT 635 639 role role NN 640 642 of of IN 643 647 EKLF EKLF NNP 648 650 in in IN 651 654 the the DT 655 668 developmental developmental JJ 669 679 regulation regulation NN 680 682 of of IN 683 686 the the DT 687 692 human human JJ 693 705 gamma-globin gamma-globin NN 706 710 gene gene NN 711 713 we we PRP 714 723 interbred interbreed VBD 724 728 EKLF EKLF NNP 729 742 heterozygotes heterozygote NNS 743 744 ( ( ( 744 747 +/- +/- SYM 747 748 ) ) ) 749 753 with with IN 754 758 mice mouse NNS 759 768 harboring harbor VBG 769 770 a a DT 771 776 human human JJ 777 788 beta-globin beta-globin NN 789 794 yeast yeast NN 795 805 artificial artificial JJ 806 816 chromosome chromosome NN 817 826 transgene transgene NN 826 827 . . . 828 830 We we PRP 831 835 find find VBP 836 840 that that IN 841 843 in in IN 844 847 the the DT 848 855 absence absence NN 856 858 of of IN 859 863 EKLF EKLF NNP 863 864 , , , 865 870 while while IN 871 876 human human JJ 877 888 beta-globin beta-globin NN 889 899 expression expression NN 900 902 is be VBZ 903 915 dramatically dramatically RB 916 923 reduced reduce VBN 923 924 , , , 925 937 gamma-globin gamma-globin NN 938 949 transcripts transcript NNS 950 953 are be VBP 954 962 elevated elevate VBN 963 976 approximately approximately RB 977 983 5-fold 5-fold RB 983 984 . . . 985 993 Impaired impaired JJ 994 1003 silencing silencing NN 1004 1006 of of IN 1007 1019 gamma-globin gamma-globin NN 1020 1030 expression expression NN 1031 1041 identifies identify VBZ 1042 1046 EKLF eklf NN 1047 1049 as as IN 1050 1053 the the DT 1054 1059 first first JJ 1060 1073 transcription transcription NN 1074 1080 factor factor NN 1081 1094 participating participate VBG 1095 1109 quantitatively quantitatively RB 1110 1112 in in IN 1113 1116 the the DT 1117 1129 gamma-globin gamma-globin NN 1130 1132 to to TO 1133 1144 beta-globin beta-globin NN 1145 1151 switch switch NN 1151 1152 . . . 1153 1156 Our our PRP$ 1157 1165 findings finding NNS 1166 1169 are be VBP 1170 1180 compatible compatible JJ 1181 1185 with with IN 1186 1187 a a DT 1188 1199 competitive competitive JJ 1200 1205 model model NN 1206 1208 of of IN 1209 1218 switching switching NN 1219 1221 in in IN 1222 1227 which which WDT 1228 1232 EKLF EKLF NNP 1233 1241 mediates mediate VBZ 1242 1244 an an DT 1245 1250 adult adult JJ 1251 1265 stage-specific stage-specific JJ 1266 1277 interaction interaction NN 1278 1285 between between IN 1286 1289 the the DT 1290 1301 beta-globin beta-globin NN 1302 1306 gene gene NN 1307 1315 promoter promoter NN 1316 1319 and and CC 1320 1323 the the DT 1324 1329 locus locus NN 1330 1337 control control NN 1338 1344 region region NN 1345 1349 that that WDT 1350 1358 excludes exclude VBZ 1359 1362 the the DT 1363 1375 gamma-globin gamma-globin NN 1376 1380 gene gene NN 1380 1381 . . .