Regulation of Gene Expression in Eukaryotes

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• ??????????

Regulation of Gene Expression in Eukaryotes
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• 1970?,????40(simian virus 40, SV40)???????????????
  ?,?????????????????

• 1975?D. Pribonow??T7??????

• 1982?C. Benoist?P. Chambon???SV40?????????

• 1983?,W.S. Dynan?R. Tjian????????????AP1?

• 1986?,J.Clarke?Chambon??????????SV40????????????

• 1990??,????-???????????????

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(No Transcript)
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(No Transcript)
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???
??????
Control of Transcription Initiation
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?????????
????
???? ????? mRNA??
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????????????

• ????????

• ???????????????

• ?????????????

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??????????????????DNA????

• ??????????DNA?????????DNA????????????????????,????
  ???????????????????????

• ???????-???????????????????,?????????????????? ?

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• ??????????(cis-acting elements)?????(promoter)????
  ??????????? ?

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(?)?????TATA?/????CpG??????????????

• ????????????????(transcription initiation
  site?transcription start site)????????????RNA?????
  ??????DNA???

• ??????????(core sequences)??????????2535
  bp?,?????TATA??,???TATA?(TATA box),?????TATA???TAT
  AAAA???TATA????????????,?RNA???II?????????????

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• ??????????????????,?????(initiator,Inr),?????????

• ????????(5?)Y-Y-A1-N-T/A-Y-Y-Y(3?)Y?????C?????T
  ,N??????,T/A??T?A?

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• ????????????????????,??????5????mRNA?

• ????????????,?????????????

• ????TATA?????,?????????100 bp???20?50?????CG??,???
  CpG?(CpG island)?

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(?)?????????????????

• ???????(promoter-proximal elements, ?upstream
  promoter elements)?????TATA????DNA??,???????,?????
  ????TATA?????RNA??????????,????????????,??????????
  ??????
• ??????

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(?)????????RNA???II???
???(enhancer)
?????????????,??????????????DNA??????,?????????(u
pstream activator sequences, UASs)?

• ?????????????????????

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• ???????

• ????????????,???????????????,?????????????????????
  ?

• ?????????????????,?100 nt?50 000nt,???????????????
  ???

????????????????????
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(?)???????????
?????????(silencer)
?????????????,???????????,???????????
??DNA?????????,???????????????????,???????????????
???
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???????????????????????
????(transcription factors)
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• ??????

RNA???????????????????,?????????????,??3?RNA??????
??????
?????????????????????????????
??????

• ??????????????,?????????????

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(?)?????????DNA???

1. ??-??-??????DNA??????

????? (homeodomain,HD)
??-??-?? (helix-turn-helix,HTH)
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2. ??????????DNA???????
C2H2???(Zinc finger)
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????ß??
Zn2
a??
DNA??
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3. ?????????DNA??????????
?????(leucine zipper)
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4. ????-?-????????DNA??????????
????-?-?? (basic helix-loop-helix,bHLH)
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5. ???????DNA
??????DNA????,?????-?????DNA??????????????????????
,??-????,??????????,????DNA???????????????
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(?)?????????-?????????
??????bHLH?????????????(?)??(?)?????(?)???(heterod
imer)????????????????
????????????????????????????,????????????RNA??????
?????????????????
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??????????????3?

• ???????????(glutamine-rich activation domains)
• ??????????(proline-rich activation domains)
• ??????????(acidic activation domains)?

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????(repressor protein)
????DNA???,??????????????????
????????????DNA???,???????-????????,??????????????
?????
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????????????????????

• ????????????????

• ?????

???????????????????????? ??????????????????????
????
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????????????????????????????????

• ??????????????????????,???????????????????????????
  ???

• ????????????,????????????????,???????????????????

• ??????????????????????????????????DNA?????????????
  ??????

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(?)????????????????
????????????????????????

• ????(heterochromatin)????????

• ????(euchromatin)??????????????,????????5-???1000
  nt????????(hypersensitive sites)?????????????????
  ??,????????????????????????????

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??????????????????????????????

• ?????????(H2A,H2B,H3,H4)??????????????,???????????
  ??,?????????????????????

• ????DNA?CpG??(CpG?)??????????5-??????????,????????
  ???????????????

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• ?????(chromatin remodeling)

??????????????????????????????????????????????????
???????????? ?

• ????????

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?????
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• ??????

????????????????????
???????????(histone acetyl transferases,
HATs),?????????(histone acetylase)????????????????
???????,????????DNA?????
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?????????????????????????????????????????
??????????(histone deacetylase)?????????,????????
??????
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(?)?????????RNA????????????????????
RNA???II????????????????????????????????
?????????????UASs??? ??????????????? ??????(coac
tivator)?/????(medicator)???????/RNA???II?????????
?????????????
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??????????????,?????????????????,?????????????????
?????
??,??????????????????,?TFIID?TFIIA,?????????????,?
?????????????(transcription initiation
complex),?????
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(No Transcript)
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??????????????????????RNA???????,???????
???(twisting)
???????DNA???????,???????????RNA?????,
??????????????/?????????????RNA???????
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???(sliding)
?DNA??,?????????DNA?????????,?????
???(looping)
??DNA??????????,???????RNA?????????,???????????/??
???????
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????????????????????????????????,???????????,?????
-????????DNA???????????????(hormone response
elements, HREs),???????????????,?????????????
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???????????
?? ??????
???(androgen) GG(A/T)ACAN2TGTTCT
????? (glucocorticoid) GGTACAN3TGTTCT
??? (retinoic acid) AGGTCAN5AGGTCA
???D (vitamin D) AGGTCAN3AGGTCA
????? (thyroid hormone) AGGTCAN3AGGTCA
????A (retinoid X) AGGTCANAGGTCANAGGTCANAGGTCA
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(?)?????????????????
??????????????????
??????????????????DNA????
?????????????????DNA??????,???????????????????????
,???????????
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??????????????????
????????????
??????????????(repressive chromatin remodeling
complexes)
????????????
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? ? ? ?????
Posttranscriptional Controls
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??????mRNA 5?????3??????????
?????,??????mRNA??5?????3???poly(A)??? ?
5?????3???poly(A)??????????
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5????????
??????mRNA??????????
???mRNA??????????????,????????????????
???mRNA??????????
?5???????????mRNA???????????? ?
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poly(A)????
poly(A)?????????????,??mRNA????,??????????????????
mRNA???poly(A)?,??????????mRNA??,?????mRNA??????
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??????????????????????
?????????????????????(alternative RNA
splicing)??,?????????????????mRNAs,??????????
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???????mRNA??????
mRNA
Pre-mRNA
????mRNA
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????????????????????????? ??????????????????????
RNA?????????
????????????????
?????????????????????????????????????
??????????????????????????????????
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??RNA??????RNA???????
??mRNAs???????(editing)?
????????????4?U??,???????????????
?????????????????????????RNA??,?3????? poly(U),
?5?????mRNAs????????,?????RNA(guide
RNA)???RNA???????????,???3???U???????mRNAs?
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??RNA??????????
?????1/5?????mRNAs????????????mRNAs??1??????mRNA?
???????????????,????????????(nuclear export
receptors)????9nm??????
????RNA?????????????????
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????RNA?????????????
????mRNA???????,????????????????????????
????????????????????????
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?????????mRNA?3??????(3?untranslated region,
3?UTR)?

• ?????

mRNA?????????????????(motor proteins)?,?????ATP???
????????????????,??????????(anchor proteins)???

• ?????

mRNA????????????,???????????????

• ?????

mRNA????????????????,??????????????
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mRNA???3???????
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??mRNA??????????????
????????mRNA???????????????????
???????mRNA??????????
??????????????????????????
??????????mRNA ????????????
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????mRNA???????,????mRNA?????????

• poly(A)???????????

• mRNA??????????,???????poly(A)??????,????30?A?,5???
  ???,mRNA????????

• ??mRNA???3?UTR????????????????,?????poly(A)??????

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• ???????????????

• ??poly(A)???mRNA??????????????mRNA???3?UTR????????
  ?????

??
??????(transferrin receptor, TfR) mRNA??
3?UTR??(stem-loop)???????(iron-response
element,IRE)?
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IRE-BP???????mRNA??????
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?????poly(A)???????????
??????,???poly(A)?????????????
???????????????
?????????mRNA???3'????10-30????(A),???????????????
??????????,?????mRNA ????????,poly(A)?????????mRNA
??,????????????
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?????????mRNA???????mRNA????
???????mRNA?? (nonsense-mediated mRNA decay, NMD)
?????????????????UAA?UAG?UGA??????????????????50
nt??,mRNA??????????????????????????(premature
termination codons, PTC),????????????????????
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???????mRNA???
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??

• ????????mRNA???????????????? ,??mRNA??????????????
  ?????? ?

• NMD?????????????,????????????DNA??????????????????
  ??

• ????????????????,?????????mRNA?NMD??????,?????????
  ??????

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??RNA?????????????
RNA??
??????????????RNAs (small RNAs)??????????????????R
NAs?mRNAs(???3?UTR)????,??mRNA????????,?mRNA??????
???????(silence)?
??
???????????????????????????RNA??????????????? ?
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miRNA ?siRNA??mRNA????
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???
? ? ? ?
Translation Control
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???????????????????
???????????????,???(??)????eIF-2(eukaryotic
initiation factor,eIF-2)??????
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(No Transcript)
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????mRNA 5??3????????????????
????????????mRNA?5????????,??????????????mRNA???3?
UTR,????3?poly(A)??5???????????????
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IRE-BP????mRNA?????
????
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??????mRNA??????????

• ????????????,??????????????????AUG??????,?????AUG
  ,????????????(leaky scanning),?????mRNA???????????
  ???????????????????,????????????????????????????

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• ????????(upstream open reading frames ,
  uORFs)???mRNA ???,?????AUG???(5?UTR)??????AUG,???
  ?????????????????????,???????????????????????

?? ???????,???AUG??????????AUG????????????,??????
????????????????