Regulation of human protein S gene (PROS1) transcription Wolf, Cornelia de
19
0
0
Hele tekst
(2) &KDSWHU. . 5HJXODWRUVRI3526WUDQVFULSWLRQDSLORWVWXG\. 'H:ROI&-)%HUWLQD50DQG9RV+/.
(3)
(4) 5HJXODWRUVRI3526WUDQVFULSWLRQDSLORWVWXG\. 6XPPDU\ 7KH IXQFWLRQRIDQWLFRDJXODQW SURWHLQ 6 36
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Ƣ 7UDQVIHFWLRQLQWR+H/DFHOOVRID3526SURPRWHUUHSRUWHU JHQHFRQVWUXFW ZLWKD SURPRWHUOHQJWKRIESDQG FDQGLGDWHWUDQVFULSWLRQ IDFWRUV FRQILUPHGWKDWERWK6SDQG &(%3ƢDUHSRWHQWDFWLYDWRUV RIWKH 3526SURPRWHU 3526SURPRWHUDFWLYLW\ZDVDOVR LQIOXHQFHG HLWKHUSRVLWLYHO\RUQHJDWLYHO\E\)2;$ $3DQG$3DQGWKH DQGURJHQ UHFHSWRU7KH UHVXOWVRIWKLVVWXG\SURYLGHLQGLFDWLRQV DV WRZKLFKHIIHFWRUV PD\SOD\DUROH LQ 3526WUDQVFULSWLRQDO UHJXODWLRQLQYLYRDQGWKHUHIRUHSURYLGHDVWDUWLQJSRLQWIRUIXWXUH UHVHDUFKLQWRWKHWUDQVFULSWLRQDOUHJXODWLRQRI36OHYHOV. .
(6) &KDSWHU. ,QWURGXFWLRQ $QWLFRDJXODQW 3URWHLQ6 36
(7) LVDYLWDPLQ .GHSHQGHQWSODVPDJO\FRSURWHLQ ZKLFK IXQFWLRQVDVDQRQHQ]\PDWLFFRIDFWRU WR DFWLYDWHGSURWHLQ& $3&
(8) LQWKHSURWHLQ& DQWLFRDJXODQWSDWKZD\
(9) 36LVSURGXFHG PDLQO\E\ WKHKHSDWRF\WHVLQWKHOLYHU
(10) EXW DOVR DWORZOHYHOVE\PDQ\RWKHUFHOOW\SHVLQ WKHERG\
(11) ,QSDWLHQWVZLWKOLYHUGLVHDVH 36 SODVPDOHYHOVDUHQRWUHGXFHGWRWKHVDPHH[WHQWDVWKRVHRIWKHVWUXFWXUDOO\UHODWHGYLWDPLQ. GHSHQGHQWFRDJXODWLRQIDFWRUV
(12) ,QWKHVH FLUFXPVWDQFHV VLJQLILFDQWDPRXQWV RI36DUH WKRXJKWWREHSURGXFHGDQGUHOHDVHGE\PHJDNDU\RF\WHV
(13) DQGWKHYDVFXODU HQGRWKHOLXP
(14) . 3URWHLQ6P51$LVWUDQVFULEHGIURPWKH 3526JHQHRQFKURPRVRPH
(15) (DUO\ VWXGLHVLQWRWKHWUDQVFULSWLRQDOLQLWLDWLRQRI 3526LQGLFDWHG WKDWWUDQVFULSWLRQLVJHQHUDWHG IURP PXOWLSOHVWDUWVLWHVZLWKLQWKH7$7$ER[OHVVSURPRWHU RIWKLVJHQH
(16) :HUHFHQWO\ FRQILUPHG DQGH[WHQGHGWKHVHDVVXPSWLRQV E\ GHPRQVWUDWLQJWKDW3526WUDQVFULSWLRQLV JHQHUDOO\GLUHFWHGIURPRQHRIIRXU PDMRUWUDQVFULSWLRQVWDUWVLWHVORFDWHGESES ESDQGESXSVWUHDPIURPWKH WUDQVODWLRQDOVWDUWFRGRQUHVSHFWLYHO\
(17) +DOODQG FRZRUNHUVSUHVHQWHGDQDEVWUDFW DW WKHPHHWLQJRIWKH,QWHUQDWLRQDO6RFLHW\RI7KURPERVLV DQG +DHPRVWDVLV ,67+
(18) LQ UHSRUWLQJ WKHUHJXODWLRQRI3526 WUDQVFULSWLRQE\PXOWLSOH WUDQVFULSWLRQIDFWRUV
(19) $QLQGXFWLRQRI3526 SURPRWHUDFWLYLW\LQYLWURZDVGHPRQVWUDWHG LQFRWUDQVIHFWLRQVRI3526SURPRWHUUHSRUWHUJHQHFRQVWUXFWVZLWKH[SUHVVLRQYHFWRUV FRQWDLQLQJF'1$VIRU&&$$7(QKDQFHU%LQGLQJ3URWHLQ &(%3
(20) ơ'%LQGLQJ 3URWHLQ '%3
(21) )RUNKHDG %R[$ )2;$
(22) +HSDWRF\WH 1XFOHDU )DFWRU +1)
(23) DQGURJHQ UHFHSWRU $5
(24) HVWURJHQ UHFHSWRU (5
(25) DQGJOXFRFRUWLFRLGUHFHSWRU *5
(26) 7KHRQO\RWKHU VWXG\WKDW LQYHVWLJDWHG WKHUHJXODWLRQRIWKH 3526SURPRWHUVKRZHGELQGLQJWRDQGLQGXFWLRQRIWKH 3526SURPRWHUE\6SDQGELQGLQJRI )2;$
(27) . ,QWKLVSLORWVWXG\ZHWHVWHGVHOHFWHGFDQGLGDWHWUDQVFULSWLRQIDFWRUVIRUWKHDELOLW\WR LQIOXHQFH 3526SURPRWHUDFWLYLW\LQYLWUR&RWUDQVIHFWLRQVRIHSLWKHOLDOFDUFLQRPDFHOOOLQH +H/DZLWKD3526 SURPRWHUUHSRUWHUJHQHFRQVWUXFWDQGH[SUHVVLRQYHFWRUV FRQWDLQLQJ WKH F'1$IRU&(%3Ƣ)2;$ +1)Ƣ
(28) +1) 2QHFXW
(29) '%3S $FWLYDWRU3URWHLQ $3
(30) 6SHFLILFLW\SURWHLQ 6S
(31) DQG6SUHVXOWHG LQLQFUHDVHGSURPRWHU DFWLYLW\ ,QFRQWUDVW. .
(32) 5HJXODWRUVRI3526WUDQVFULSWLRQDSLORWVWXG\ SURPRWHUDFWLYLW\ZDV GHFUHDVHGLQWKHSUHVHQFHRI)2;$ +1)ƣ
(33) +1)MXQIRVS DQGWKH $5. ([SHULPHQWDOSURFHGXUHV 3K\ORJHQHWLF IRRWSULQWLQJDQGSURPRWHUSUHGLFWLRQV IRUWKH 3526SURPRWHUUHJLRQ7KH ·XSVWUHDP VHTXHQFHVIRU 3526IURPKXPDQFKLPSDQ]HHUKHVXV PRQNH\ GRJPRXVH UDWSLJDQG FRZ ZHUHHLWKHUJHQHUDWHGE\DXWRPDWHGVHTXHQFLQJ KXPDQ
(34) RU DVVHPEOHG WKURXJKDOLJQPHQW RI NQRZQVHTXHQFHVZLWKWKHQXFOHRWLGH DQGWUDFH GDWDEDVHVDWWKH1DWLRQDO&HQWHUIRU %LRWKHFKQRORJ\,QIRUPDWLRQ 1&%,
(35) ZZZQFELQOPQLKJRY
(36) 7KHVHTXHQFHVZHUHDOLJQHG DQG DQDO\]HGZLWKWKH9,67$ VRIWZDUH JHQRPHOEOJRYYLVWD
(37) ZKHUHQHFHVVDU\WKH DOLJQPHQWVZHUHDGMXVWHGPDQXDOO\$GGLWLRQDOWUDQVFULSWLRQIDFWRUELQGLQJVLWH DQDO\VHVZHUH GRQHZLWKWKH,)7,PLUDJH VRIWZDUH ZZZLIWLRUJ
(38) DQG0DW,QVSHFWRUSURIHVVLRQDO ZZZJHQRPDWL[GH
(39) 3URPRWHUSUHGLFWLRQVZHUH GRQH ZLWK WKHSURVFDQVRIWZDUHDWWKH ELPDVGFUWQLKJRYZHEVLWH 3ODVPLGV 7KH 3526SURPRWHUUHSRUWHU JHQH OXFLIHUDVH
(40) FRQVWUXFW36ZDV GHVFULEHGSUHYLRXVO\ &KDSWHU RIWKLVWKHVLV
(41) 7KHH[SUHVVLRQYHFWRUVFRQWDLQLQJF'1$VIRU WUDQVFULSWLRQIDFWRUVRIPXULQHRULJLQ S6&7&(%3Ƣ
(42) S069&(%3ơ
(43) S(&( +1)
(44) S&09'%3
(45) SF'1$)2;$
(46) +1)ơ Ƣ ƣ
(47)
(48) ZHUH GHVFULEHGSUHYLRXVO\SF'1$+1)ZDVJHQHUDWHGIURPS/(16+1)
(49) DQG SF'1$+1)ơZDV JHQHUDWHGIURPS%-+1)ơ
(50) 7KHH[SUHVVLRQ YHFWRUVFRQWDLQLQJ F'1$VIRU WUDQVFULSWLRQ IDFWRUVRIKXPDQRULJLQ S69$52
(51) S&09$3
(52) S&09 6S
(53) DQGS&096S
(54) S569FMXQ DQGS569FIRV
(55) S&09S
(56) S&09S DQGS&09S
(57) ZHUHSUHYLRXVO\GHVFULEHGS7UDFHU*5 ZDVJHQHUDWHGIURPS569*5
(58) DQGSF'1$+1)ƢZDVJHQHUDWHGE\LQVHUWLRQ RIWKHRULJLQDO+1)ƢF'1$
(59) LQWR SF'1$7KHF'1$V IRUFRQVWLWXWLYHO\ DFWLYH KXPDQ(5ơDQG (5ƢLQH[SUHVVLRQYHFWRU S6KXWWOHZHUHJHQHUDWHGDWWKH +XPDQDQG&OLQLFDO*HQHWLFVGHSDUWPHQWRIWKH/HLGHQ 8QLYHUVLW\0HGLFDO&HQWUH DQG ZHUHNLQGO\SURYLGHG E\'U:LOOHPVYDQ'LMN &HOOFXOWXUH 7KHKXPDQFHUYL[HSLWKHOLDOFDUFLQRPDFHOOOLQH+H/DZDVSXUFKDVHGIURP WKH$PHULFDQ7\SH &XOWXUH&ROOHFWLRQ $7&& 0DQDVVDV9$
(60) &HOOVZHUHJURZQLQ0LQLPDO HVVHQWLDO PHGLXP 0(0
(61) )HWDO%RYLQH6HUXP )%6
(62) ƬJPOSHQLFLOOLQƬJPO VWUHSWRP\FLQ DQG[0(0QRQHVVHQWLDODPLQRDFLGV DOOSXUFKDVHGIURP*LEFR,QYLWURJHQ
(63) . .
(64) &KDSWHU 5HSRUWHUJHQHDVVD\V&HOOVZHUH WUDQVIHFWHGDWFRQIOXHQF\ (DFKWUDQVIHFWLRQZDV SHUIRUPHGLQWULSOLFDWHLQZHOOVSODWHV7UDQVIHFWLRQV ZHUHFDUULHGRXWXVLQJ ƬO7I[ OLSLGV 3URPHJD
(65) SHUƬJ WUDQVIHFWHG'1$,QHDFKWUDQVIHFWLRQQJ36DQGQJ WUDQVFULSWLRQIDFWRUH[SUHVVLRQYHFWRUZDVXVHG&RQWURO YHFWRUS5/69 3URPHJD
(66) H[SUHVVLQJWKH 5HQLOODOXFLIHUDVHZDV FRWUDQVIHFWHGIRU FRUUHFWLRQRIWUDQVIHFWLRQHIILFLHQF\LQ D UDWLRWRWRWDOWUDQVIHFWHG'1$7KHFHOOH[WUDFWVZHUHKDUYHVWHGKRXUV DIWHU WUDQVIHFWLRQ/XFLIHUDVHOHYHOV ZHUHPHDVXUHG ZLWKWKHGXDOOXFLIHUDVHDVVD\NLW 3URPHJD /HLGHQWKH 1HWKHUODQGV
(67) LQWKH/% OXPLQRPHWHU %HUWKROG%XQGRRUD$XVWUDOLD
(68) DFFRUGLQJWRWKHPDQXIDFWXUHUVUHFRPPHQGDWLRQV. 5HVXOWV &RQVHUYHGVHTXHQFHVLQWKH3526 SURPRWHUUHJLRQ7KHES·XSVWUHDPVHTXHQFHVIRU 3526 IURPKXPDQ FKLPSDQ]HHUKHVXVPRQNH\ GRJPRXVHUDWSLJDQG FRZZHUHDOLJQHG ZLWKWKHP9,67$VRIWZDUH DQGDQDO\VHGIRUSXWDWLYHWUDQVFULSWLRQIDFWRUELQGLQJVLWHV )LJXUH
(69) $KLJKGHJUHHRIFRQVHUYDWLRQDPRQJVWDOO VSHFLHVZDVIRXQGLQDUHJLRQDSSUR[LPDWHO\ HQFRPSDVVLQJ ESWR8SVWUHDPIURPWKLVSRLQWWKH 3526SURPRWHUVHTXHQFHIURP PRXVHDQG UDW GHYLDWHGIURPWKHRWKHUVSHFLHVZKLFKNHSWDKLJKKRPRORJ\XSWRES 6HTXHQFHVIURPUKHVXVPRQNH\ FKLPSDQ]HHDQGKXPDQZHUHKLJKO\KRPRORJRXV WKURXJKRXW WKHH[DPLQHG UHJLRQ. ,QWKHILUVWUHJLRQ
(70) WZRVWUHWFKHVRI VHTXHQFHZLWKDYHU\KLJKKRPRORJ\ZHUH IRXQGQDPHO\DQG*&ER[HVDUHORFDWHGDWDQGESDQGDUH SXWDWLYHELQGLQJVLWHV IRU WKH6SIDPLO\RIWUDQVFULSWLRQIDFWRUV WKH FRQVHQVXVVHTXHQFHEHLQJ .***&**55< ··
(71)
(72) $WSRVLWLRQVWKURXJKVLWHVIRU67$7
(73) FRQVHQVXV 77 Q
(74) $$DQG&(%3Ƣ
(75) FRQVHQVXV5157.11*0$$.ZHUHLGHQWLILHG6LQFH WKHVH VLWHVKDYHUHPDLQHGLQWKH 3526 SURPRWHUWKURXJKRXWHYROXWLRQLW PD\EHDVVXPHGWKDW WKH\ DUHLPSRUWDQWLQWKHUHJXODWLRQ RIWKHWUDQVFULSWLRQDODFWLYLW\RIWKH 3526SURPRWHU 7KHUHIRUH WKHVHVLWHVDUHREYLRXVFDQGLGDWHV IRUIXWXUHVWXGLHV. )XUWKHUFRPSXWDWLRQDO DQDO\VHVZHUHGRQHIRUWKH3526SURPRWHU UHJLRQDOVRWDNLQJLQWR DFFRXQWWKHORFDWLRQRIWUDQVFULSWLRQVWDUWVLWHV7KHSURVFDQVRIWZDUH FDOFXODWHGDSXWDWLYH SURPRWHUZLWKDVWDUWVLWHDWEXWGLGQRWLGHQWLI\WKHRWKHUVWDUWVLWHV WKDWZHUH .
(76) 5HJXODWRUVRI3526WUDQVFULSWLRQDSLORWVWXG\. )LJXUH3K\ORJHQHWLFDOLJQPHQWRIWKH3526SURPRWHUVHTXHQFH6HTXHQFHVIURP KXPDQ FKLPSDQ]HHUKHVXVPRQNH\FRZ GRJ PRXVH DQG UDWZHUHUHWULHYHGIURPWKH DUFKLYHVDW WKH 1&%, 1XPEHULQJLVDFFRUGLQJWRWKHKXPDQVHTXHQFHZLWKWKHILUVW QXFOHRWLGHRIWKHWUDQVODWLRQDOVWDUWFRGRQ EHLQJ&RQV FRQVHUYHGVHTXHQFH 7KH HQER[HGQXFOHRWLGHVDUHWKHWUDQVFULSWLRQVWDUWVLWHVIRXQG LQUHIHUHQFH .
(77) &KDSWHU H[SHULPHQWDOO\ IRXQGE\XVSUHYLRXVO\
(78) 7DEOHJLYHV WKH FRQVHQVXVELQGLQJVLWHDQG FRQVHUYDWLRQOHYHORIVHOHFWHGWUDQVFULSWLRQIDFWRUELQGLQJVLWHVZLWKLQWKH 3526 VHTXHQFHXVLQJ YDULRXVSURJUDPV. 7). /RFDWLRQ. &RQVHQVXV. &RQVHUYDWLRQ. 6RIWZDUH. $3. . <&6&&01666. KFKU. . 6S. . .***&**55<. KFKU. . &5(%$7). . 7*$&*70$. KFKU. . )2;$. . 757775<77. KFKUFRG. . 67$7 &(%3Ƣ. . 771111 1
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
(80) &(%3ơ1)ƪ% DQG WKHQHXUDOO\H[SUHVVHG VLOHQFHU165)7KHVH VLWHV DUHQRWLQFOXGHGLQWKH WDEOH 2QWKHRWKHUKDQGWKH *5VLWHZKLFKLVDOVR LQFRPSOHWHtV PHQWLRQHGEHFDXVHLWLVLQD KLJKO\FRQVHUYHGUHJLRQ. 5DWLRQDOHIRU WKHVHOHFWLRQRI WUDQVFULSWLRQIDFWRUV7UDQVFULSWLRQIDFWRUVZHUHVHOHFWHGRQEDVLVRI WKHSUHVHQFHRIDSXWDWLYHELQGLQJVLWHLQWKH 3526VHTXHQFH 6S6S)2;$ &(%3Ƣ$3 *5
(81) RQWKHLU UHODWLRQ WRWKHSULRU FDWHJRU\ )2;$ )2;$&(%3ơ(5 $5
(82) RUWKHLU OLYHUVSHFLILFH[SUHVVLRQ +1)+1) +1))2;$ )2;$ )2;$ &(%3Ƣ '%3
(83) $QDGGLWLRQDODUJXPHQWIRULQFOXGLQJWKHVWHURLG UHFHSWRUV (5DQG$5LV .
(84) 5HJXODWRUVRI3526WUDQVFULSWLRQDSLORWVWXG\ JLYHQE\WKHIDFWWKDWSODVPD36OHYHOVDUHQHJDWLYHO\LQIOXHQFHGE\IHPDOHVWHURLGKRUPRQHV
(85) 7KHPHFKDQLVPE\ZKLFKWKLVGRZQUHJXODWLRQRI36OHYHOVRFFXUVLVXQNQRZQ. 7KHPDMRUSURLQIODPPDWRU\F\WRNLQHVLQWHUOHXNLQ ,/
(86) DQG 7XPRU 1HFURVLV)DFWRU ơ 71)ơ
(87) DFWLYDWHWUDQVFULSWLRQ IDFWRUV $3 MXQDQGIRV
(88) DQG 1)ƪ% S SS
(89)
(90) ,QFRPSOHWHELQGLQJVLWHVIRUWKHVH'1$ELQGLQJSURWHLQVDUH ORFDWHGLQWKH36VHTXHQFH (YHQ WKRXJKWKH FRQVHQVXVHVDUHLQFRPSOHWH ZHLQFOXGHGWKHH[SUHVVLRQYHFWRUV IRU WKHVH WUDQVFULSWLRQIDFWRUVLQRXUVWXG\PDLQO\IRU WZRUHDVRQV)LUVWO\36OHYHOVLQKHSDWRPD +HS*
(91) DQGHQGRWKHOLDO 09(&+89(&
(92) FHOO FXOWXUHDUH XSUHJXODWHGE\ LQWHUOHXNLQ ,/
(93) DQGGRZQUHJXODWHG E\71)ơ WKXVOLQNLQJ36WRWKHLQIODPPDWRU\UHVSRQVH
(94) 6HFRQGO\ UHFHQWSXEOLFDWLRQVLQGLFDWHWKDWIUHHSODVPD36PD\DFWRQLQIODPPDWLRQ E\IDFLOLWDWLQJWKH XSWDNH RIHDUO\DSRSWRWLFFHOOV E\PDFURSKDJHV
(95) DQGWKDW36LQFRPSOH[ ZLWKFRPSOHPHQW EELQGLQJSURWHLQ &%3
(96) GLUHFWVFRPSOHPHQWWRWKHVXUIDFHRIDSRSWRWLF FHOOV
(97) . 3526 SURPRWHUDFWLYLW\LVPRGXODWHGE\YDULRXVOLYHUVSHFLILF DQG XELTXLWRXVWUDQVFULSWLRQIDFWRUV +H/DHSLWKHOLDOFDUFLQRPDFHOOVZHUHFRWUDQVIHFWHGZLWK 3526SURPRWHUUHSRUWHU FRQVWUXFW 36DQGDWUDQVFULSWLRQIDFWRUH[SUHVVLRQYHFWRU )LJXUH
(98) 7UDQVFULSWLRQIDFWRUV6SDQG 6SXSUHJXODWHG 3526 SURPRWHUDFWLYLW\DQGIROGUHVSHFWLYHO\ /RZHUEXWDOVR VLJQLILFDQWVWLPXODWRU\HIIHFWV ZHUHVKRZQIRU&(%3Ƣ IROG
(99) )2;$ IROG
(100) +1) IROG
(101) S IROG
(102) DQG$3 IROG
(103) 1HJDWLYHHIIHFWRUVZHUHWKHFRPSRQHQWVRI$3 MXQ DQG IRV
(104) WKHSVXEXQLWRIWKH1)ƪ% FRPSOH[ DQGWKH$5)2;$DQG +1)VOLJKWO\ GRZQUHJXODWHG 3526SURPRWHU DFWLYLW\WKH PHDVXUHGUHGXFWLRQLQSURPRWHUDFWLYLW\ZDV VLJQLILFDQWEXWWKHHIIHFWZDVPDUJLQDO. ,GHQWLFDOWUDQVIHFWLRQDVVD\VZHUHDOVRFDUULHG RXWZLWKKHSDWRF\WHV +HS*FHOOV
(105) ZKLFK DUHWKHPDLQVRXUFHRISODVPD36 LQYLYRUHVXOWLQJLQDVLPLODU DOEHLWOHVVSURQRXQFHGSDWWHUQ RISURPRWHULQGXFWLRQ UHVXOWVQRWVKRZQ
(106) %HFDXVH HQGRJHQRXVOLYHUVSHFLILFWUDQVFULSWLRQ IDFWRUV DUHDOUHDG\SUHVHQWLQWKHQXFOHXVRI KHSDWRF\WHVSRVVLEO\LQVXIILFLHQWOHYHOVIRU PD[LPDO 3526 SURPRWHUUHJXODWLRQWKHHIIHFWRIWKLVFDWHJRU\RIWUDQVFULSWLRQIDFWRUVRQ SURPRWHUDFWLYLW\LVTXHQFKHG DQG URXWLQHO\XQGHUHVWLPDWHG. .
(107) &KDSWHU. .
(108) 5HJXODWRUVRI3526WUDQVFULSWLRQDSLORWVWXG\. 'LVFXVVLRQ 7KLVSLORWVWXG\LVDJRRGH[DPSOHRIWKH DGGHGYDOXHRISK\ORJHQHWLFIRRWSULQWLQJLQ ORFDWLQJDQGLGHQWLI\LQJSRWHQWLDOWUDQVFULSWLRQDOHIIHFWRUVLQSURPRWHUVWXGLHV,QRXUVSHFLHV FRPSDULVRQIRUWKH363526SURPRWHUWZRPDMRUVLWHVDWDQG SURYHGWREHKLJKO\ FRQVHUYHG WKURXJKRXWHYROXWLRQ )LJXUH
(109) 7KHIDFWRUV&(%3ƢDQG 6S6SWKDWKDYH FRQVHQVXV ELQGLQJVLWHVZLWKLQWKHVHUHJLRQVZHUH VXEVHTXHQWO\IRXQGWR EHWKH PDMRUWUDQVFULSWLRQDODFWLYDWRUVRIWKH36SURPRWHUUHSRUWHU JHQHFRQVWUXFW )LJXUH
(110) 0RVWOLNHO\ 6S WUDQVDFWLYDWHVWKH 3526 SURPRWHUE\ELQGLQJ WRPXOWLSOHVLWHVZLWKLQWKH SURPRWHUZKHUHDVRQO\DVLQJOHELQGLQJVLWHIRU&(%3ƢLVFRQWDLQHGLQWKH36VHTXHQFH 7DEOH
(111) 6SLVDXELTXLWRXVO\SUHVHQWWUDQVFULSWLRQIDFWRU
(112) DQGPD\WKHUHIRUHEHLQYROYHG LQWKHFRQVWLWXWLYHH[SUHVVLRQRI 35262QWKHRWKHUKDQG &(%3ƢLVUHVWULFWHGWRFHUWDLQ WLVVXHVDPRQJVWZKLFKWKHOLYHU
(113) DQGLV SUREDEO\LQYROYHGLQWLVVXHVSHFLILFUHJXODWLRQ RI36OHYHOV 7KHVDPHKROGVIRUWKHOLYHUVSHFLILFWUDQVFULSWLRQIDFWRU)2;$
(114) RIZKLFK WKHELQGLQJVLWHLVDOVRKLJKO\ FRQVHUYHGDQG ZKLFKDOVRXSUHJXODWHG 36SURPRWHUDFWLYLW\ +1) PLOGO\LQGXFHG36DFWLYLW\:HGLG QRWILQGWKH FRQVHQVXVIRU+1) ·$$57&$ $7$:·
(115) LQWKH36SURPRWHUUHJLRQ. 7KH $3SURWHLQVMXQDQGIRVDVZHOODVWKH WUDQVDFWLYDWLRQVXEXQLWSRI1)N% QHJDWLYHO\LQIOXHQFHG36DFWLYLW\ )LJ
(116) 2QWKHRWKHUKDQG&(%3ƢDNQRZQPHGLDWHU RI,/VLJQDOOLQJ HQKDQFHG36DFWLYLW\7KHVWLPXODWRU\DQGLQKLELWRU\HIIHFWVRQ36OHYHOV LQYLWURGHVFULEHGIRU,/DQG71)ơ UHVSHFWLYHO\PD\WKXVEHPHGLDWHGWKURXJKWKHVH SURWHLQV
(117) ,QWHUHVWLQJO\ $3&ZDVVKRZQWRLQKLELWWKH DFWLYDWLRQDQGWUDQVORFDWLRQRI WKH1)ƪ%FRPSOH[ DQG$3WRWKHQXFOHXVWKHUHE\LQKLELWLQJ71)ơSURGXFWLRQDQGUHOHDVH E\PRQRF\WHV
(118) $OWKRXJK WKHUHLVQRHYLGHQFH WRVXJJHVWDUHJXODWLRQRI36OHYHOVE\$3& LWLVWHPSWLQJ WRVSHFXODWHWKDW$3&FRXOGSRVLWLYHO\LQIOXHQFH 3526WUDQVFULSWLRQ WKURXJKD VLPLODUPHFKDQLVP. :KDWKDVEHHQ FOHDUO\ VKRZQLVWKDW36SODVPDOHYHOVDUH GRZQUHJXODWHGE\IHPDOH KRUPRQHV 7KHPHFKDQLVPE\ ZKLFKWKLVRFFXUVKDVQRWEHHQVWXGLHGWKXV FRWUDQVIHFWLRQV RI 36ZLWKWKH VWHURLG UHFHSWRUVZHUHRIVSHFLDOLQWHUHVW:H GLGQRWILQGDJRRG FRQVHQVXV IRUDQ\QXFOHDUVWHURLG UHFHSWRUVLQWKH 3526 VHTXHQFH WKH *5VLWH LQ7DEOHLV UDWKHUZHDNSRRU
(119) EXWQHYHUWKHOHVVLQFOXGHGH[SUHVVLRQYHFWRUVIRUWKH FRQVWLWXWLYHO\DFWLYH .
(120) &KDSWHU (5ơDQG(5Ƣ WKH *5DQGWKH$5LQRXUSLORWVWXG\ ,QFRQWUDVWWRWKHUHVXOWVREWDLQHG E\ +DOODQGFRZRUNHUV
(121) ZHIRXQG WKDWWKH$5GRZQUHJXODWHG36DFWLYLW\ZKHUHDVWKH *5 DQG (5KDGQR LQIOXHQFH$OWKRXJKWKH (5ZDVORQJFRQVLGHUHGWREHWKHVROHPHGLDWRURI HVWURJHQDFWLRQVHYHUDO ILQGLQJV VKRZ WKDWHVWURJHQFDQGLUHFWO\DFWLYDWH$5IXQFWLRQ
(122) 2XUUHVXOWVIRU WKH$5DUHWKXVLQOLQHZLWKWKHLQKLELWRU\LQIOXHQFHRIIHPDOH VWHURLG KRUPRQHVRQ36SODVPDOHYHOVKRZHYHUZHKDGH[SHFWHG WRVHHDQHIIHFWZLWKWKH(5 DVZHOO. $V DFHOOGLIIHUHQWLDWLRQIDFWRUWKHWUDQVFULSWLRQIDFWRU$3LVLPSHUDWLYHIRUWKHQRUPDO GHYHORSPHQWRIWKHQHXUDO FUHVWLQHPEU\RJHQHVLV
(123) ,QDGXOWKRRG$3P51$LVSUHVHQWLQ VHYHUDO WLVVXHV ZLWKKLJKHVWOHYHOVRFFXUULQJLQ IHPDOHUHSURGXFWLYHRUJDQVH\HVNLQDQGOLYHU KWWS KDUYHVWHUHPEOGHKDUYHVWHU
(124) 7KH 3526SURPRWHU KDVDFRQVHUYHG$3ELQGLQJVLWH DQGLQFRWUDQVIHFWLRQV$3HQKDQFHG 3526 SURPRWHUDFWLYLW\DOEHLW PDUJLQDOO\ IROG
(125) 7KLVLVRILQWHUHVWVLQFH 36LVSUHVHQWLQEUDLQ
(126) DQGKDVEHHQVKRZQWRSURWHFWDJDLQVW QHXURQDOFHOOGHDWKXSRQ LVFKHPLFLQMXU\
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
(128) . 5HIHUHQFHV :DONHU)-5HJXODWLRQ RIDFWLYDWHGSURWHLQ& E\DQHZSURWHLQ$SRVVLEOHIXQFWLRQIRUERYLQH SURWHLQ6-%LRO&KHP . :DONHU)-5HJXODWLRQ RIDFWLYDWHGSURWHLQ& E\SURWHLQ67KHUROHRISKRVSKROLSLGLQIDFWRU9D LQDFWLYDWLRQ-%LRO&KHP . . (VPRQ&79LJDQR' $QJHOR6 ' $QJHOR$&RPS3& $QWLFRDJXODWLRQSURWHLQV &DQG6 $GY([S0HG%LRO . .
(129) 5HJXODWRUVRI3526WUDQVFULSWLRQDSLORWVWXG\ )DLU'60DUODU5$%LRV\QWKHVLVDQGVHFUHWLRQ RI IDFWRU9,,SURWHLQ& SURWHLQ6DQGWKH3URWHLQ &LQKLELWRUIURP DKXPDQKHSDWRPDFHOOOLQH%ORRG )DLU'60DUODU5$/HYLQ(*+XPDQHQGRWKHOLDOFHOOVV\QWKHVL]HSURWHLQ6%ORRG . 6FKZDU]+3+HHE0-:HQFHO'UDNH-'*ULIILQ-+,GHQWLILFDWLRQ DQGTXDQWLWDWLRQ RISURWHLQ6 LQKXPDQSODWHOHWV%ORRG . . 2JXUD07DQDEH11LVKLRND- 6X]XNL.6DLWR +%LRV\QWKHVLVDQGVHFUHWLRQ RIIXQFWLRQDO SURWHLQ 6 E\DKXPDQPHJDNDU\REODVWLF FHOOOLQH 0(*
(130) %ORRG . 6WHUQ'%UHWW- +DUULV.1DZURWK33DUWLFLSDWLRQRIHQGRWKHOLDOFHOOVLQWKHSURWHLQ&SURWHLQ6 DQWLFRDJXODQWSDWKZD\ WKHV\QWKHVLVDQGUHOHDVHRI SURWHLQ6-&HOO%LRO . 0DOP-+H ;+ %MDUWHOO$6KHQ /$EUDKDPVVRQ 3$'DKOElFN%9LWDPLQ.GHSHQGHQWSURWHLQ 6LQ/H\GLJFHOOVRIKXPDQWHVWLV %LRFKHP- 3W
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lFN%HWDO,VRODWLRQDQGVHTXHQFH RIWKHF'1$IRUKXPDQSURWHLQ6DUHJXODWRU RIEORRGFRDJXODWLRQ 3URF1DWO$FDG6FL86$ 'H:ROI&-&XSHUV50%HUWLQD 509RV+/,QLWLDWLRQ RI3URWHLQ6P51$V\QWKHVLVLQ KXPDQ OLYHUDQGYDULRXV FHOOOLQHV-7KURPE+DHPRVW . .
(133) &KDSWHU +DOO$-3HDNH,5DQG:LQVKLS3 5,GHQWLILFDWLRQ RIPXOWLSOHHOHPHQWVUHJXODWLQJ WUDQVFULSWLRQ RIWKHSURWHLQ6JHQH 7KURPE+DHPRVW DEVWUDFW
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
(135) SURWHLQDQG 6SIDPLO\PHPEHUV VXSHUDFWLYDWLRQE\ 5EUHTXLUHVDPLQRDFLGVQHFHVVDU\ IRUJURZWK VXSSUHVVLRQ3URF1DWO$FDG6FL86$ %RKPDQQ'%RV7-$GPRQ $ 1LVKLPXUD79RJW3.7MLDQ5+XPDQ SURWRRQFRJHQHFMXQ HQFRGHVD'1$ ELQGLQJ SURWHLQ ZLWKVWUXFWXUDODQGIXQFWLRQDOSURSHUWLHVRIWUDQVFULSWLRQIDFWRU $36FLHQFH /LX-3HUNLQV1'6FKPLG501DEHO*-6SHFLILF1)NDSSD%VXEXQLWVDFWLQFRQFHUWZLWK7DWWR VWLPXODWHKXPDQ LPPXQRGHILFLHQF\YLUXVW\SHWUDQVFULSWLRQ-9LURO 6FKPLW]0/%DHXHUOH3$7KHSVXEXQLWLVUHVSRQVLEOHIRUWKH VWURQJ WUDQVFULSWLRQDFWLYDWLQJ SRWHQWLDO RI1)NDSSD%(0%2- . .
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lFN%9LWDPLQ.GHSHQGHQW SURWHLQ6ORFDOL]LQJFRPSOHPHQWUHJXODWRU &EELQGLQJ SURWHLQWR WKHVXUIDFHRIDSRSWRWLFFHOOV-,PPXQRO 'DKOElFN%9LOORXWUHL[%25HJXODWLRQ RI EORRGFRDJXODWLRQE\ WKHSURWHLQ&DQWLFRDJXODQW SDWKZD\ QRYHOLQVLJKWVLQWRVWUXFWXUHIXQFWLRQUHODWLRQVKLSVDQG PROHFXODUUHFRJQLWLRQ $UWHULRVFOHU7KURPE9DVF%LRO 6FKUHP+.OHPSQDXHU-%RUODN -/LYHUHQULFKHG WUDQVFULSWLRQIDFWRUVLQOLYHUIXQFWLRQDQG GHYHORSPHQW3DUW,, WKH&(%3V DQG'VLWHELQGLQJSURWHLQLQFHOOF\FOHFRQWUROFDUFLQRJHQHVLV FLUFDGLDQJHQHUHJXODWLRQOLYHUUHJHQHUDWLRQDSRSWRVLVDQGOLYHUVSHFLILFJHQHUHJXODWLRQ 3KDUPDFRO5HY .DHVWQHU.+7KHKHSDWRF\WHQXFOHDUIDFWRU +1)RU)2;$
(137) IDPLO\LQPHWDEROLVP7UHQGV (QGRFULQRO0HWDE <XNVHO02NDMLPD.8FKLED0+RULXFKL62NDEH+$FWLYDWHGSURWHLQ&LQKLELWV OLSRSRO\VDFFKDULGHLQGXFHGWXPRU QHFURVLVIDFWRUDOSKD SURGXFWLRQE\LQKLELWLQJDFWLYDWLRQ RIERWK QXFOHDUIDFWRUNDSSD%DQGDFWLYDWRUSURWHLQLQKXPDQPRQRF\WHV7KURPE+DHPRVW . .
(138) &KDSWHU <HK60L\DPRWR+6KLPD+&KDQJ&)URPHVWURJHQWRDQGURJHQUHFHSWRU DQHZ SDWKZD\IRU VH[KRUPRQHVLQSURVWDWH3URF1DWO$FDG6FL86$ /DQ]LQR0'H $PLFLV)0F3KDXO0-0DUVLFR63DQQR0/$QGR6(QGRJHQRXVFRDFWLYDWRU $5$LQWHUDFWV ZLWKHVWURJHQUHFHSWRUDOSKD (5DOSKD
(139) DQG PRGXODWHVWKHIXQFWLRQDO (5DOSKDDQGURJHQUHFHSWRULQWHUSOD\LQ0&)FHOOV-%LRO&KHP 7KLQ7+:DQJ /.LP(&ROOLQV//%DVDYDSSD 5&KDQJ&,VRODWLRQDQGFKDUDFWHUL]DWLRQRI DQGURJHQUHFHSWRUPXWDQW $5 0 /
(140) ZLWK K\SHUVHQVLWLYLW\WREHWDHVWUDGLROWUHDWPHQW -%LRO&KHP +LOJHU(YHUVKHLP.0RVHU06FKRUOH+%XHWWQHU55HJXODWRU\ UROHVRI$3WUDQVFULSWLRQ IDFWRUVLQYHUWHEUDWHGHYHORSPHQWDSRSWRVLVDQGFHOOF\FOHFRQWURO *HQH +H;6KHQ/%MDUWHOO$'DKOEl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
(141)
(142)
(143)
GERELATEERDE DOCUMENTEN
GHSHQGHQWSURWHLQ6DQGFRPSOHPHQWFRPSRQHQW&EELQGLQJ SURWHLQ3URF1DWO$FDG6FL86$ 'DKOElFN%,QKLELWLRQ RISURWHLQ &DFRIDFWRUIXQFWLRQ RIKXPDQDQGERYLQH SURWHLQ 6E\&E ELQGLQJ SURWHLQ-%LRO&KHP
)RUWKHILUVWWLPHZH UHSRUW WKHSUHVHQFHRI D3URWHLQ 6 36 WUDQVFULSW UHVXOWLQJIURP
UHVHDUFKLQWRWKHFLVDFWLQJ HOHPHQWVJRYHUQLQJ 3526 WUDQVFULSWLRQKDVWRGDWHEHHQKDPSHUHGE\DFRQWURYHUV\ UHJDUGLQJWKHSUHVHQFHRISRVVLEOH DGGLWLRQDOH[RQV XSVWUHDP
&RFN\ GH :ROI LVRSVHSWHPEHU JHERUHQ WH /HLGHQ 1DKHWEHKDOHQYDQKDDU9:2
With the identification of three main transcription start sites (-147, -117, -100) and many additional unique sites in human liver, human umbilical vein endothelial cells (HUVEC),
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of
Note: To cite this publication please use the final published version (if applicable)... 5HJXODWLRQRIKXPDQ3URWHLQ6JHQH 3526 WUDQVFULSWLRQ 3URHIVFKULIW
Furthermore, exposure of hippocampal organotypic slices to a 30 nM corticosterone pulse has been shown to reduce the dendritic tree in the CA1 subregion in a delayed manner
