248:
that conferred resistance to rifampicin. Three clusters of mutations were identified, cluster I at codons 507-533, cluster II at codons 563-572, and cluster III at codon 687. The majority of these mutations are located within an 81 base pair(bp) region in cluster I dubbed the "Rifampicin
Resistance
307:
gene which are susceptible to mutations are typically well conserved, indicating they are important for life. This makes it very likely that mutations within these regions have some effect on the overall fitness of the organism. These physiological changes can include a reduced rate of growth,
252:
There are additional mutations which can occur in the β subunit of the polymerase which are located away from the rifampicin binding site that can also result in mild resistance. Potentially indicating that the shape of these areas may affect the formation of the rifampicin binding site.
249:
Determining Region (RRDR)". This resistance is typically associated with a mutation wherein a base in the DNA is substituted for another one and the new sequence codes for an amino acid with a large side chain that inhibits the rifampicin molecules from binding to the polymerase.
232:
binds to a site near the fork in the β subunit and prevents the polymerase from transcribing more than two or three base pairs of any RNA sequence and stopping production of proteins within the cell. Bacteria with mutations in the proper loci along the
308:
increased sensitivity to increases or decreases in temperature, and alterations to the properties of RNA chain elongation and transcription termination. Such changes are not universal across all bacteria, though. A mutation in codon 450 of
345:
and implicated in virulence of the bacteria. Mutations also impact promoter binding, elongation, termination, and transcription-coupled repair processes in the RNA polymerase itself. Because of this,
330:
and in transcription elongation. At the same time enzymes involved in ATP production, cell division, and lipid metabolism are all downregulated, or expressed at a lower than normal level.
953:
Telenti A, Imboden P, Marchesi F, Lowrie D, Cole S, Colston MJ, Matter L, Schopfer K, Bodmer T (March 1993). "Detection of rifampicin-resistance mutations in
Mycobacterium tuberculosis".
349:
mutations were used to study transcription mechanisms before interest shifted to their ability to impart antibiotic resistance. Particular mutations can even result in strains of
1573:
120:
326:
mutations have been observed to increase expression of enzymes which are involved in metabolizing carbohydrates, as well as enzymes involved in the
289:
195:
that confer resistance to rifamycins do so by altering the protein's drug-binding residues, thereby reducing affinity for these antibiotics.
73:
869:
Jin DJ, Gross CA (July 1988). "Mapping and sequencing of mutations in the
Escherichia coli rpoB gene that lead to rifampicin resistance".
768:
Alifano P, Palumbo C, Pasanisi D, TalĂ A (May 2015). "Rifampicin-resistance, rpoB polymorphism and RNA polymerase genetic engineering".
998:"Molecular characterization of rpoB mutations conferring cross-resistance to rifamycins on methicillin-resistant Staphylococcus aureus"
1521:
1066:
54:
266:, the rifamycin-resistant mutations most commonly encountered involve codons 516, 526, and 531 (numbered, by convention, as in
1689:
1212:
1444:
1553:
1661:
217:, also inhibits PEP, showing that the complex found in plants is very similar to the homologous enzyme in bacteria.
1815:
1759:
1416:
906:"Allele-specific rpoB PCR assays for detection of rifampin-resistant Mycobacterium tuberculosis in sputum smears"
1754:
1469:
1411:
1842:
1773:
1514:
1464:
33:
1432:
1406:
822:"The impact of drug resistance on Mycobacterium tuberculosis physiology: what can we learn from rifampicin?"
531:"Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center"
1578:
1059:
362:
1793:
1092:
262:
1289:
1225:
1195:
1173:
275:). These mutations result in high rifampicin resistance with a relatively low loss of fitness. For
1896:
1837:
1625:
1538:
1507:
1083:
1075:
372:
102:
1798:
1615:
1600:
1390:
1079:
353:
which grow better in the presence of rifampicin than they do when the antibiotic is not present.
341:, potentially indicating increased production of phthiocerol dimycocerosate, a lipid produced by
1803:
1728:
1620:
1299:
1052:
647:"A comparison of rpoB and 16S rRNA as markers in pyrosequencing studies of bacterial diversity"
321:
1718:
1703:
1583:
1483:
1478:
1346:
1248:
277:
1825:
1723:
1641:
1380:
1294:
1260:
1154:
658:
601:
542:
476:
Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, Darst SA (March 2001).
441:
Floss HG, Yu TW (February 2005). "Rifamycin-mode of action, resistance, and biosynthesis".
140:
8:
1651:
1363:
1331:
1217:
1191:
338:
107:
1044:
662:
605:
546:
525:
Feklistov A, Mekler V, Jiang Q, Westblade LF, Irschik H, Jansen R, Mustaev A, Darst SA,
183:, making it the second-largest polypeptide in the bacterial cell. It is targeted by the
1786:
1669:
1132:
978:
846:
821:
681:
646:
622:
589:
588:
Case RJ, Boucher Y, Dahllöf I, Holmström C, Doolittle WF, Kjelleberg S (January 2007).
565:
530:
526:
507:
930:
905:
494:
477:
380:
mutations can increase the production of antibiotic by bacteria with those mutations.
1451:
1027:
1022:
997:
970:
966:
935:
886:
882:
851:
785:
727:
686:
627:
570:
499:
458:
423:
327:
61:
1870:
921:
1906:
1373:
1356:
1017:
1009:
982:
962:
925:
917:
878:
841:
833:
777:
717:
676:
666:
617:
609:
590:"Use of 16S rRNA and rpoB genes as molecular markers for microbial ecology studies"
560:
550:
511:
489:
450:
413:
268:
78:
781:
1847:
1684:
1530:
1237:
722:
705:
671:
281:, the rifamycin-resistant mutation most commonly encountered involves codon 526.
150:
1674:
1646:
1447:
1435:
1385:
535:
Proceedings of the
National Academy of Sciences of the United States of America
172:
356:
In bacteria which are used to produce naturally occurring antibiotics such as
1890:
1875:
1562:
1149:
555:
478:"Structural mechanism for rifampicin inhibition of bacterial rna polymerase"
1901:
1749:
1679:
1548:
1031:
1013:
939:
855:
789:
731:
690:
631:
574:
503:
462:
427:
357:
974:
890:
1852:
1781:
1336:
1304:
1207:
613:
214:
90:
837:
418:
401:
1810:
1488:
1182:
1137:
1127:
1122:
1117:
1112:
367:
229:
114:
85:
454:
312:
leads to a minor loss of fitness, while the corresponding mutation in
66:
1144:
203:
184:
1830:
1820:
1744:
1351:
1341:
199:
188:
1499:
996:
Wichelhaus TA, Schäfer V, Brade V, Böddinghaus B (November 1999).
903:
1566:
1311:
1178:
995:
704:
Börner T, Aleynikova AY, Zubo YO, Kusnetsov VV (September 2015).
176:
179:-encoded RNA polymerase (PEP). It codes for 1342 amino acids in
1107:
645:
Vos M, Quince C, Pijl AS, de
Hollander M, Kowalchuk GA (2012).
475:
49:
904:
Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O (July 2003).
202:
gene, which is commonly used as the molecular marker to study
1588:
1368:
1220:
706:"Chloroplast RNA polymerases: Role in chloroplast biogenesis"
703:
524:
952:
1269:
1200:
587:
284:
In addition to imparting resistance to rifampicin, certain
168:
767:
298:
1558:
1074:
644:
337:
mutations in the rpoB gene can significantly upregulate
240:
Initial studies were done by Jin and Gross to generate
710:
Biochimica et
Biophysica Acta (BBA) - Bioenergetics
819:
225:In a bacterium without the proper mutation(s) in
1888:
210:gene can be used to study microbial diversity.
989:
1515:
1060:
198:Some bacteria contain multiple copies of the
316:results in bacteria barely able to survive.
256:Nucleic acid probes can detect mutations in
820:Koch A, Mizrahi V, Warner DF (March 2014).
213:An inhibitor of transcription in bacteria,
1670:Precursor mRNA (pre-mRNA / hnRNA)
1522:
1508:
1067:
1053:
1021:
929:
845:
721:
680:
670:
621:
564:
554:
493:
417:
399:
288:mutations have been identified in 70% of
868:
518:
434:
260:that confer rifampicin resistance. For
19:DNA-directed RNA polymerase subunit beta
469:
440:
299:Physiological Effects of rpoB Mutations
1889:
594:Applied and Environmental Microbiology
1690:Histone acetylation and deacetylation
1503:
1213:Histone acetylation and deacetylation
1048:
1002:Antimicrobial Agents and Chemotherapy
910:Antimicrobial Agents and Chemotherapy
763:
761:
1755:Ribosome-nascent chain complex (RNC)
815:
813:
811:
809:
807:
805:
803:
801:
799:
759:
757:
755:
753:
751:
749:
747:
745:
743:
741:
402:"Resistance to rifampicin: a review"
395:
393:
1529:
237:gene are resistant to this effect.
171:encodes the β subunit of bacterial
13:
826:Emerging Microbes & Infections
220:
206:. In these cases, the single-copy
187:family of antibacterials, such as
14:
1918:
796:
738:
390:
1760:Post-translational modification
1417:Archaeal transcription factor B
946:
922:10.1128/AAC.47.7.2231-2235.2003
897:
862:
400:Goldstein BP (September 2014).
697:
638:
581:
1:
782:10.1016/j.jbiotec.2014.11.024
495:10.1016/S0092-8674(01)00286-0
383:
967:10.1016/0140-6736(93)90417-F
883:10.1016/0022-2836(88)90517-7
871:Journal of Molecular Biology
723:10.1016/j.bbabio.2015.02.004
672:10.1371/journal.pone.0030600
7:
363:Saccharopolyspora erythraea
10:
1923:
1093:Transcriptional regulation
406:The Journal of Antibiotics
263:Mycobacterium tuberculosis
1863:
1772:
1737:
1711:
1702:
1660:
1634:
1608:
1599:
1537:
1460:
1425:
1399:
1324:
1290:Transcription coregulator
1282:
1259:
1236:
1226:Histone acetyltransferase
1196:Histone methyltransferase
1174:Histone-modifying enzymes
1172:
1165:
1100:
1091:
146:
136:
131:
127:
113:
101:
96:
84:
72:
60:
48:
40:
28:
23:
18:
1821:sequestration (P-bodies)
770:Journal of Biotechnology
373:Amycolatopsis orientalis
290:Vancomycin Intermediate
1799:Gene regulatory network
1391:Internal control region
556:10.1073/pnas.0802822105
121:genomic: 4.18 - 4.19 Mb
1804:cis-regulatory element
1014:10.1128/aac.43.11.2813
322:Neisseria meningitidis
1484:Intrinsic termination
1249:DNA methyltransferase
278:Staphylococcus aureus
1826:alternative splicing
1816:Post-transcriptional
1642:Transcription factor
1261:Chromatin remodeling
614:10.1128/AEM.01177-06
1750:Transfer RNA (tRNA)
1218:Histone deacetylase
1208:Histone demethylase
1192:Histone methylation
838:10.1038/emi.2014.17
663:2012PLoSO...730600V
606:2007ApEnM..73..278C
547:2008PNAS..10514820F
419:10.1038/ja.2014.107
339:polyketide synthase
303:The regions of the
175:and the homologous
1864:Influential people
1843:Post-translational
1662:Post-transcription
529:(September 2008).
1884:
1883:
1768:
1767:
1698:
1697:
1574:Special transfers
1497:
1496:
1452:RNA polymerase II
1320:
1319:
1278:
1277:
455:10.1021/cr030112j
328:citric acid cycle
160:
159:
156:
155:
1914:
1709:
1708:
1606:
1605:
1524:
1517:
1510:
1501:
1500:
1374:Response element
1357:Response element
1170:
1169:
1098:
1097:
1069:
1062:
1055:
1046:
1045:
1036:
1035:
1025:
993:
987:
986:
961:(8846): 647–50.
950:
944:
943:
933:
901:
895:
894:
866:
860:
859:
849:
817:
794:
793:
765:
736:
735:
725:
701:
695:
694:
684:
674:
642:
636:
635:
625:
585:
579:
578:
568:
558:
522:
516:
515:
497:
473:
467:
466:
443:Chemical Reviews
438:
432:
431:
421:
397:
295:(VISA) strains.
269:Escherichia coli
191:. Mutations in
129:
128:
36:
34:Escherichia coli
16:
15:
1922:
1921:
1917:
1916:
1915:
1913:
1912:
1911:
1897:Gene expression
1887:
1886:
1885:
1880:
1859:
1794:Transcriptional
1764:
1733:
1694:
1685:Polyadenylation
1656:
1630:
1595:
1589:Protein→Protein
1540:
1533:
1531:Gene expression
1528:
1498:
1493:
1468:
1462:
1456:
1421:
1395:
1316:
1274:
1255:
1238:DNA methylation
1232:
1176:
1161:
1087:
1073:
1042:
1040:
1039:
994:
990:
951:
947:
902:
898:
867:
863:
818:
797:
766:
739:
702:
698:
643:
639:
586:
582:
541:(39): 14820–5.
523:
519:
474:
470:
439:
435:
398:
391:
386:
351:M. tuberculosis
343:M. tuberculosis
335:M. tuberculosis
310:M. tuberculosis
301:
223:
221:Drug resistance
32:
12:
11:
5:
1920:
1910:
1909:
1904:
1899:
1882:
1881:
1879:
1878:
1873:
1871:François Jacob
1867:
1865:
1861:
1860:
1858:
1857:
1856:
1855:
1850:
1840:
1835:
1834:
1833:
1828:
1823:
1813:
1808:
1807:
1806:
1801:
1791:
1790:
1789:
1778:
1776:
1770:
1769:
1766:
1765:
1763:
1762:
1757:
1752:
1747:
1741:
1739:
1735:
1734:
1732:
1731:
1726:
1721:
1715:
1713:
1706:
1700:
1699:
1696:
1695:
1693:
1692:
1687:
1682:
1677:
1672:
1666:
1664:
1658:
1657:
1655:
1654:
1649:
1647:RNA polymerase
1644:
1638:
1636:
1632:
1631:
1629:
1628:
1623:
1618:
1612:
1610:
1603:
1597:
1596:
1594:
1593:
1592:
1591:
1586:
1581:
1571:
1570:
1569:
1551:
1545:
1543:
1535:
1534:
1527:
1526:
1519:
1512:
1504:
1495:
1494:
1492:
1491:
1486:
1481:
1475:
1473:
1458:
1457:
1455:
1454:
1448:RNA polymerase
1442:
1436:RNA polymerase
1429:
1427:
1423:
1422:
1420:
1419:
1414:
1409:
1403:
1401:
1397:
1396:
1394:
1393:
1388:
1383:
1378:
1377:
1376:
1371:
1361:
1360:
1359:
1354:
1349:
1344:
1339:
1328:
1326:
1322:
1321:
1318:
1317:
1315:
1314:
1309:
1308:
1307:
1302:
1297:
1286:
1284:
1280:
1279:
1276:
1275:
1273:
1272:
1266:
1264:
1257:
1256:
1254:
1253:
1252:
1251:
1243:
1241:
1234:
1233:
1231:
1230:
1229:
1228:
1223:
1210:
1205:
1204:
1203:
1188:
1186:
1167:
1163:
1162:
1160:
1159:
1158:
1157:
1152:
1142:
1141:
1140:
1135:
1130:
1125:
1120:
1115:
1104:
1102:
1095:
1089:
1088:
1072:
1071:
1064:
1057:
1049:
1038:
1037:
1008:(11): 2813–6.
988:
945:
896:
861:
795:
737:
696:
637:
580:
517:
468:
433:
388:
387:
385:
382:
300:
297:
222:
219:
173:RNA polymerase
158:
157:
154:
153:
148:
144:
143:
138:
134:
133:
125:
124:
117:
111:
110:
105:
99:
98:
94:
93:
88:
82:
81:
76:
70:
69:
64:
58:
57:
52:
46:
45:
42:
38:
37:
30:
26:
25:
21:
20:
9:
6:
4:
3:
2:
1919:
1908:
1905:
1903:
1900:
1898:
1895:
1894:
1892:
1877:
1876:Jacques Monod
1874:
1872:
1869:
1868:
1866:
1862:
1854:
1851:
1849:
1846:
1845:
1844:
1841:
1839:
1838:Translational
1836:
1832:
1829:
1827:
1824:
1822:
1819:
1818:
1817:
1814:
1812:
1809:
1805:
1802:
1800:
1797:
1796:
1795:
1792:
1788:
1785:
1784:
1783:
1780:
1779:
1777:
1775:
1771:
1761:
1758:
1756:
1753:
1751:
1748:
1746:
1743:
1742:
1740:
1736:
1730:
1727:
1725:
1722:
1720:
1717:
1716:
1714:
1710:
1707:
1705:
1701:
1691:
1688:
1686:
1683:
1681:
1678:
1676:
1673:
1671:
1668:
1667:
1665:
1663:
1659:
1653:
1650:
1648:
1645:
1643:
1640:
1639:
1637:
1633:
1627:
1624:
1622:
1619:
1617:
1614:
1613:
1611:
1607:
1604:
1602:
1601:Transcription
1598:
1590:
1587:
1585:
1582:
1580:
1577:
1576:
1575:
1572:
1568:
1564:
1560:
1557:
1556:
1555:
1554:Central dogma
1552:
1550:
1547:
1546:
1544:
1542:
1536:
1532:
1525:
1520:
1518:
1513:
1511:
1506:
1505:
1502:
1490:
1487:
1485:
1482:
1480:
1477:
1476:
1474:
1471:
1466:
1459:
1453:
1449:
1446:
1443:
1441:
1437:
1434:
1431:
1430:
1428:
1424:
1418:
1415:
1413:
1410:
1408:
1405:
1404:
1402:
1398:
1392:
1389:
1387:
1384:
1382:
1379:
1375:
1372:
1370:
1367:
1366:
1365:
1362:
1358:
1355:
1353:
1350:
1348:
1345:
1343:
1340:
1338:
1335:
1334:
1333:
1330:
1329:
1327:
1323:
1313:
1310:
1306:
1303:
1301:
1298:
1296:
1293:
1292:
1291:
1288:
1287:
1285:
1281:
1271:
1268:
1267:
1265:
1262:
1258:
1250:
1247:
1246:
1245:
1244:
1242:
1239:
1235:
1227:
1224:
1222:
1219:
1216:
1215:
1214:
1211:
1209:
1206:
1202:
1199:
1198:
1197:
1193:
1190:
1189:
1187:
1184:
1180:
1175:
1171:
1168:
1164:
1156:
1155:trp repressor
1153:
1151:
1150:lac repressor
1148:
1147:
1146:
1143:
1139:
1136:
1134:
1131:
1129:
1126:
1124:
1121:
1119:
1116:
1114:
1111:
1110:
1109:
1106:
1105:
1103:
1099:
1096:
1094:
1090:
1085:
1081:
1077:
1076:Transcription
1070:
1065:
1063:
1058:
1056:
1051:
1050:
1047:
1043:
1033:
1029:
1024:
1019:
1015:
1011:
1007:
1003:
999:
992:
984:
980:
976:
972:
968:
964:
960:
956:
949:
941:
937:
932:
927:
923:
919:
916:(7): 2231–5.
915:
911:
907:
900:
892:
888:
884:
880:
876:
872:
865:
857:
853:
848:
843:
839:
835:
831:
827:
823:
816:
814:
812:
810:
808:
806:
804:
802:
800:
791:
787:
783:
779:
775:
771:
764:
762:
760:
758:
756:
754:
752:
750:
748:
746:
744:
742:
733:
729:
724:
719:
715:
711:
707:
700:
692:
688:
683:
678:
673:
668:
664:
660:
657:(2): e30600.
656:
652:
648:
641:
633:
629:
624:
619:
615:
611:
607:
603:
600:(1): 278–88.
599:
595:
591:
584:
576:
572:
567:
562:
557:
552:
548:
544:
540:
536:
532:
528:
521:
513:
509:
505:
501:
496:
491:
488:(6): 901–12.
487:
483:
479:
472:
464:
460:
456:
452:
449:(2): 621–32.
448:
444:
437:
429:
425:
420:
415:
412:(9): 625–30.
411:
407:
403:
396:
394:
389:
381:
379:
375:
374:
369:
365:
364:
359:
354:
352:
348:
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340:
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329:
325:
323:
317:
315:
311:
306:
296:
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293:
287:
282:
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270:
265:
264:
259:
254:
250:
247:
244:mutations in
243:
238:
236:
231:
228:
218:
216:
211:
209:
205:
201:
196:
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190:
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182:
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167:
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152:
149:
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118:
116:
112:
109:
106:
104:
100:
95:
92:
89:
87:
83:
80:
77:
75:
74:RefSeq (Prot)
71:
68:
65:
63:
59:
56:
53:
51:
47:
43:
39:
35:
31:
27:
22:
17:
1853:irreversible
1738:Key elements
1635:Key elements
1549:Genetic code
1539:Introduction
1439:
1041:
1005:
1001:
991:
958:
954:
948:
913:
909:
899:
877:(1): 45–58.
874:
870:
864:
829:
825:
773:
769:
716:(9): 761–9.
713:
709:
699:
654:
650:
640:
597:
593:
583:
538:
534:
520:
485:
481:
471:
446:
442:
436:
409:
405:
377:
371:
361:
358:erythromycin
355:
350:
346:
342:
334:
332:
320:
318:
313:
309:
304:
302:
291:
285:
283:
276:
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234:
226:
224:
212:
207:
197:
192:
180:
164:
163:
161:
119:
1704:Translation
1541:to genetics
1461:Termination
1337:Pribnow box
1305:Corepressor
1300:Coactivator
1101:prokaryotic
215:tagetitoxin
141:Swiss-model
79:NP_418414.1
24:Identifiers
1891:Categories
1848:reversible
1811:lac operon
1787:imprinting
1782:Epigenetic
1774:Regulation
1729:Eukaryotic
1675:5' capping
1626:Eukaryotic
1489:Rho factor
1479:Terminator
1470:eukaryotic
1445:eukaryotic
1426:Elongation
1412:Eukaryotic
1400:Initiation
1183:nucleosome
1166:eukaryotic
1138:gal operon
1133:ara operon
1128:Gua Operon
1123:gab operon
1118:trp operon
1113:lac operon
1084:Eukaryotic
832:(3): e17.
527:Ebright RH
384:References
376:) certain
368:vancomycin
230:rifampicin
137:Structures
132:Search for
115:Chromosome
97:Other data
1719:Bacterial
1616:Bacterial
1465:bacterial
1433:bacterial
1407:Bacterial
1381:Insulator
1325:Promotion
1295:Activator
1145:Repressor
1080:Bacterial
776:: 60–77.
314:S. aureus
292:S. aureus
204:phylogeny
185:rifamycin
103:EC number
1831:microRNA
1745:Ribosome
1724:Archaeal
1680:Splicing
1652:Promoter
1621:Archaeal
1565: →
1561: →
1386:Silencer
1364:Enhancer
1352:CAAT box
1342:TATA box
1332:Promoter
1032:10543773
940:12821473
856:26038512
790:25481100
732:25680513
691:22355318
651:PLOS ONE
632:17071787
575:18787125
504:11290327
463:15700959
428:25118103
200:16S rRNA
189:rifampin
151:InterPro
29:Organism
1907:Enzymes
1584:RNA→DNA
1579:RNA→RNA
1567:Protein
1312:Inducer
1179:histone
983:9945266
975:8095569
891:3050121
847:3975073
682:3280256
659:Bibcode
623:1797146
602:Bibcode
566:2567451
543:Bibcode
512:8229399
246:E. coli
181:E. coli
177:plastid
147:Domains
108:2.7.7.6
86:UniProt
1108:Operon
1030:
1020:
981:
973:
955:Lancet
938:
931:161874
928:
889:
854:
844:
788:
730:
689:
679:
630:
620:
573:
563:
510:
502:
461:
426:
366:) and
91:P0A8V2
55:948488
50:Entrez
41:Symbol
1712:Types
1609:Types
1369:E-box
1221:HDAC1
1023:89569
979:S2CID
508:S2CID
1440:rpoB
1283:both
1270:CHD7
1201:EZH2
1028:PMID
971:PMID
936:PMID
887:PMID
852:PMID
786:PMID
728:PMID
714:1847
687:PMID
628:PMID
571:PMID
500:PMID
482:Cell
459:PMID
424:PMID
378:rpoB
347:rpoB
324:rpoB
305:rpoB
286:rpoB
273:rpoB
258:rpoB
242:rpoB
235:rpoB
227:rpoB
208:rpoB
193:rpoB
169:gene
165:rpoB
162:The
67:3IYD
44:rpoB
1902:RNA
1563:RNA
1559:DNA
1347:BRE
1018:PMC
1010:doi
963:doi
959:341
926:PMC
918:doi
879:doi
875:202
842:PMC
834:doi
778:doi
774:202
718:doi
677:PMC
667:doi
618:PMC
610:doi
561:PMC
551:doi
539:105
490:doi
486:104
451:doi
447:105
414:doi
333:In
319:In
62:PDB
1893::
1450::
1438::
1185:):
1082:,
1026:.
1016:.
1006:43
1004:.
1000:.
977:.
969:.
957:.
934:.
924:.
914:47
912:.
908:.
885:.
873:.
850:.
840:.
828:.
824:.
798:^
784:.
772:.
740:^
726:.
712:.
708:.
685:.
675:.
665:.
653:.
649:.
626:.
616:.
608:.
598:73
596:.
592:.
569:.
559:.
549:.
537:.
533:.
506:.
498:.
484:.
480:.
457:.
445:.
422:.
410:67
408:.
404:.
392:^
1523:e
1516:t
1509:v
1472:)
1467:,
1463:(
1263::
1240::
1194:/
1181:/
1177:(
1086:)
1078:(
1068:e
1061:t
1054:v
1034:.
1012::
985:.
965::
942:.
920::
893:.
881::
858:.
836::
830:3
792:.
780::
734:.
720::
693:.
669::
661::
655:7
634:.
612::
604::
577:.
553::
545::
514:.
492::
465:.
453::
430:.
416::
370:(
360:(
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