0 10 Thymocytes thymocyte NNS 11 18 control control VBP 19 22 the the DT 23 26 CD4 cd4 NN 27 31 gene gene NN 32 43 differently differently RB 44 48 from from IN 49 55 mature mature JJ 56 57 T t NN 58 69 lymphocytes lymphocyte NNS 69 70 . . . 72 74 We we PRP 75 83 analyzed analyze VBD 84 87 the the DT 88 96 activity activity NN 97 99 of of IN 100 103 the the DT 104 112 enhancer enhancer NN 112 113 , , , 114 117 the the DT 118 126 promoter promoter NN 127 130 and and CC 131 134 the the DT 135 143 silencer silencer NN 144 146 of of IN 147 150 the the DT 151 156 human human JJ 157 160 CD4 cd4 NN 161 165 gene gene NN 166 172 during during IN 173 174 T t NN 175 179 cell cell NN 180 191 development development NN 192 197 using use VBG 198 208 transgenic transgenic JJ 209 213 mice mouse NNS 213 214 . . . 215 233 Immunofluorescence Immunofluorescence NNP 234 241 studies study NNS 242 244 on on IN 245 251 thymic thymic JJ 252 263 populations population NNS 264 266 of of IN 267 271 mice mouse NNS 272 280 carrying carry VBG 281 291 transgenes transgene NNS 292 294 in in IN 295 302 various various JJ 303 315 combinations combination NNS 316 318 of of IN 319 324 these these DT 325 335 regulatory regulatory JJ 336 339 DNA dna NN 340 348 elements element NNS 349 357 revealed reveal VBD 358 362 that that IN 363 373 thymocytes thymocyte NNS 374 381 control control VBP 382 385 the the DT 386 389 CD4 cd4 NN 390 394 gene gene NN 395 397 in in IN 398 399 a a DT 400 409 different different JJ 410 416 manner manner NN 417 421 than than IN 422 428 mature mature JJ 429 439 peripheral peripheral JJ 440 441 T t NN 442 453 lymphocytes lymphocyte NNS 453 454 . . . 455 458 The the DT 459 470 5’-positive 5'-positive JJ 471 481 regulatory regulatory JJ 482 486 unit unit NN 486 487 , , , 488 498 consisting consist VBG 499 501 of of IN 502 505 the the DT 506 514 promoter promoter NN 515 518 and and CC 519 522 the the DT 523 524 5 5 CD 524 525 ’ ' SYM 526 534 enhancer enhancer NN 534 535 , , , 536 538 is be VBZ 539 546 already already RB 547 553 active active JJ 554 556 at at IN 557 560 the the DT 561 584 CD4-CD8-double-negative cd4-cd8-double-negative JJ 585 586 ( ( ( 586 588 DN dn JJ 588 589 ) ) ) 590 595 stage stage NN 596 598 of of IN 599 610 development development NN 610 611 . . . 612 619 However however RB 619 620 , , , 621 624 its its PRP$ 625 633 activity activity NN 634 641 becomes become VBZ 642 647 lower low JJR 648 650 in in IN 651 654 the the DT 655 670 double-positive double-positive JJ 671 674 and and CC 675 676 a a DT 677 685 fraction fraction NN 686 688 of of IN 689 692 the the DT 693 697 CD4+ cd4+ JJ 698 706 CD8int/- cd8int/- JJ 707 711 cell cell NN 712 722 population population NN 722 723 , , , 724 734 indicating indicate VBG 735 739 that that IN 740 742 an an DT 743 753 additional additional JJ 754 762 enhancer enhancer NN 762 763 , , , 764 771 located located JJ 772 774 in in IN 775 781 either either CC 782 785 the the DT 786 791 first first JJ 792 794 or or CC 795 798 the the DT 799 804 third third JJ 805 811 intron intron NN 812 814 of of IN 815 818 the the DT 819 822 CD4 cd4 NN 823 827 gene gene NN 827 828 , , , 829 831 is be VBZ 832 840 required require VBN 841 844 for for IN 845 848 CD4 cd4 NN 849 853 gene gene NN 854 864 expression expression NN 865 867 in in IN 868 872 this this DT 873 883 population population NN 883 884 . . . 885 888 The the DT 889 894 other other JJ 895 902 studied study VBN 903 913 regulatory regulatory JJ 914 921 element element NN 922 924 is be VBZ 925 928 the the DT 929 936 minimal minimal JJ 937 940 CD4 cd4 NN 941 949 silencer silencer NN 950 955 which which WDT 956 964 inhibits inhibit VBZ 965 968 CD4 cd4 NN 969 973 gene gene NN 974 984 expression expression NN 985 987 in in IN 988 998 peripheral peripheral JJ 999 1002 CD8 cd8 NN 1003 1004 T t NN 1005 1016 lymphocytes lymphocyte NNS 1016 1017 . . . 1018 1022 This this DT 1023 1031 silencer silencer NN 1032 1034 is be VBZ 1035 1043 inactive inactive JJ 1044 1046 in in IN 1047 1050 the the DT 1051 1055 most most RBS 1056 1064 immature immature JJ 1065 1067 DN dn JJ 1068 1078 thymocytes thymocyte NNS 1078 1079 , , , 1080 1085 which which WDT 1086 1094 probably probably RB 1095 1098 use use VBP 1099 1100 a a DT 1101 1109 distinct distinct JJ 1110 1118 silencer silencer NN 1119 1128 mechanism mechanism NN 1129 1131 to to TO 1132 1145 down-regulate down-regulate VB 1146 1149 CD4 cd4 NN 1150 1154 gene gene NN 1155 1165 expression expression NN 1165 1166 . . . 1167 1179 Unexpectedly unexpectedly RB 1179 1180 , , , 1181 1184 the the DT 1185 1188 CD4 cd4 NN 1189 1197 silencer silencer NN 1198 1200 is be VBZ 1201 1205 also also RB 1206 1212 active active JJ 1213 1215 in in IN 1216 1220 CD4+ cd4+ JJ 1221 1229 CD8int/- cd8int/- JJ 1230 1235 cells cell NNS 1236 1238 of of IN 1239 1242 the the DT 1243 1249 thymus thymus NN 1249 1250 , , , 1251 1259 implying imply VBG 1260 1264 that that IN 1265 1267 an an DT 1268 1281 anti-silencer anti-silencer NN 1282 1285 may may MD 1286 1288 be be VB 1289 1297 required require VBN 1298 1300 to to TO 1301 1307 resume resume VB 1308 1311 CD4 cd4 NN 1312 1322 expression expression NN 1323 1325 in in IN 1326 1330 this this DT 1331 1335 cell cell NN 1336 1346 population population NN 1346 1347 . . . 1348 1358 Altogether altogether RB 1358 1359 , , , 1360 1363 the the DT 1364 1367 CD4 cd4 NN 1368 1372 gene gene NN 1373 1375 is be VBZ 1376 1385 regulated regulate VBN 1386 1388 by by IN 1389 1396 several several JJ 1397 1405 positive positive JJ 1406 1409 and and CC 1410 1418 negative negative JJ 1419 1429 regulatory regulatory JJ 1430 1440 mechanisms mechanism NNS 1441 1446 which which WDT 1447 1451 come come VBP 1452 1456 into into IN 1457 1461 play play NN 1462 1464 in in IN 1465 1466 a a DT 1467 1482 developmentally developmentally RB 1483 1494 coordinated coordinate VBN 1495 1501 manner manner NN 1501 1502 . . .