GENETICS
'ZCORNGQHEJTQOCVKPTGIWNCVKQPFWTKPIGNQPICVKQP
56'KP[GCUV
%6&
%T[RVKE
VTCPUETKRVKQP
%T[RVKE
VTCPUETKRVKQP
UVCTVUKVG
4RF5
5GV
56'
O40#
#EGV[NCVKQP
+P[GCUVNQUUQHVJGJKUVQPGFGCEGV[NCUGEQORNGZ4RF5QTVJG*-
OGVJ[NVTCPUHGTCUG5GVTGUWNVUKPJ[RGTCEGV[NCVKQPQHVJGEQFKPITGIKQPQH
IGPGUUWEJCU56'2TQOQVGTNKMGTGIKQPUYKVJKPVJGEQFKPITGIKQPCTG
VJGPCDNGVQTGETWKV2QN++CPFEQORQPGPVUQHVJGIGPGTCNVTCPUETKRVKQP
OCEJKPGT[CPFVTCPUETKRVKQPECPDGKPKVKCVGFKPCRRTQRTKCVGN[CVVJGUG
ET[RVKEKPKVKCVKQPUKVGU6JWURTQRGTTGIWNCVKQPQHJKUVQPGCUUGODN[
FKUCUUGODN[CPFOQFKECVKQPUCTGETKVKECNVQEQPVTQNVTCPUETKRVKQPQPC
EJTQOCVKPVGORNCVG
&WTKPIVTCPUETKRVKQPGNQPICVKQPVJG
RJQURJQT[NCVGFTGUKFWGUQPVJG%6&
RTQXKFGDKPFKPIUKVGUHQTEJTQOCVKP
OQFKGTUUWEJCU5'6&
5GVKP
[GCUVCPFKGUYJKEJOGVJ[NCVGU
*-'EKGPVVTCPUETKRVKQP
TGSWKTGUEJTQOCVKPTGOQFGNNKPID[
EQORNGZGUUWEJCU59+50(CPF
45%CPFJKUVQPGEJCRGTQPGUUWEJ
CUVJG(#%6EQORNGZCPF526
0WENGQUQOGUOWUVDGFKURNCEGF
CJGCFQH2QN++CPFTGCUUGODNGF
HQNNQYKPIKVURCUUCIG*KUVQPG
OQFKECVKQPUCTGECTGHWNN[TGIWNCVGF
VQRTGXGPVKPCRRTQRTKCVG
VTCPUETKRVKQPKPKVKCVKQPHTQOYKVJKP
VJGEQFKPITGIKQPQHIGPGU
%6&
2TQOQVGTUGNGEVKQP
CPFTGEQIPKVKQP
s)CNCEVQUG
7#5)#.
#EVKXCVQT
#EVKXCVQTUTGETWKVNCTIGOWNVK
UWDWPKVEQCEVKXCVQTUUWEJCU
/GFKCVQTVJGJKUVQPG
CEGV[NVTCPUHGTCUGEQORNGZ5#)#
CPFEJTQOCVKPTGOQFGNNKPI
EQORNGZGU
UWEJCU59+50(
VJCVWUGVJGGPGTI[HTQO#62VQ
OQXGQTFKURNCEGPWENGQUQOGUCV
VJGRTQOQVGT
6CTIGVIGPG
4GEQIPKVKQP
UKVG
)GPGVTCPUETKRVKQP
UVCTVUKVG
6GTOKPCVKQP
CPFTGKPKVKCVKQP
6TCPUETKRVKQP
GNQPICVKQP
*KUVQPG
FGCEGV[NCUG
5'6&
&5+(
JGVGTQFKOGT
QH5RVCPF5RV
%JTQOCVKP
TGOQFGNNGT
6JGVTCPUETKRVKQPE[ENG
#EGV[NCVKQP
*-VTKOGVJ[NCVKQP
)#(
52QP
%6&
0'.(
2TQOQVGTRTQZKOCN
RCWUGF2QN++
2QUVJGCVUJQEM
*5(
2#42
52
52
)#(
26'(D
#UGEQPFUGTKGUQH
RJQURJQT[NCVKQPGXGPVU
ECVCN[UGFD[%&-
YKVJKP26'(DCTG
TGSWKTGFVQTGNGCUG2QN++
HTQOVJKURCWUGFUVCVG
KPVQRTQFWEVKXG
VTCPUETKRVKQPGNQPICVKQP
26'(DRJQURJQT[NCVGU
VJG52QHVJG%6&CU
YGNNCUTGUKFWGUQP0'.(
CPF&5+(
2QN++
52
52
6JGEGPVTCNE[ENGUJQYUUQOGQH
VJGOCKPUVGRUKPVTCPUETKRVKQP#V
FKGTGPVIGPGUFKGTGPVUVCIGU|QH
VJKUE[ENGECPDGVJGMG[TGIWNCVQT[
TCVGFGVGTOKPKPIUVGRU/CP[
CURGEVUCTGEQPUGTXGFCOQPI
URGEKGU
KPVJGEGPVTCNRCPGNUJWOCP
PQOGPENCVWTGKUOCKPN[WUGF1PN[C
UGNGEVKQPQHRTQVGKPUCPFEJTQOCVKP
OQFKECVKQPUCTGUJQYPVQ
KNNWUVTCVGVJGUGSWGPEGQHGXGPVU
6JGUKFGRCPGNUUJQYGZCORNGU
QHRCTVKEWNCTIGPGUQTRTQXKFG
OQTGFGVCKNHQTEGTVCKPUVCIGU
5#)#
59+50(
)GPG
VTCPUETKRVKQP
UVCTVUKVG
6TCPUETKRVKQP
GNQPICVKQP
2JQURJQT[NCVKQP
#EVKXCVQTFGRGPFGPV
/GFKCVQTCPF
59+50(TGETWKVOGPV
/GFKCVQT
2TGKPKVKCVKQP
EQORNGZ
HQTOCVKQP
2TGKPKVKCVKQPEQORNGZHQTOCVKQP
2TQOQVGT
ENGCTCPEG
2TQOQVGT
RTQZKOCNRCWUKPI
5#)#
59+50(
4GNGCUGHTQO
RTQOQVGT
RTQZKOCN
RCWUKPI
#EVKXCVQTFGRGPFGPV
5#)#TGETWKVOGPV
5#)#
26'(D
4GNGCUGHTQORTQOQVGT
RTQZKOCNRCWUKPI
)CNCEVQUG
#EGV[NCVKQP
/GFKCVQT
O40#
2JQURJQT[NCVKQP
)CN
#EVKXCVQTFGRGPFGPV
TGETWKVOGPVQHEQCEVKXCVQTU
'ZCORNGQHTGIWNCVKQPD[RQN[OGTCUGRCWUKPI
JGCVUJQEMIGPGUKP&TQUQRJKNCOGNCPQICUVGT
2TGJGCVUJQEM
%[VQRNCUO
2TG
KPKVKCVKQP
EQORNGZ
6QIGVJGTEJTQOCVKP
TGOQFGNNGTUCPF
EQCEVKXCVQTUHCEKNKVCVG
TGETWKVOGPVQH2QN++CPF
VJGIGPGTCNVTCPUETKRVKQP
HCEVQTU
)6(UVQHQTO
VJGRTGKPKVKCVKQP
EQORNGZQPVJG
RTQOQVGT
UGGENQUGWR
1TCPIGPWENGQUQOG
KPFKECVGUOQXGOGPV
QTFKURNCEGOGPV
6JGRTGKPKVKCVKQPEQORNGZRTKQTVQRTQOQVGTENGCTCPEG
6(++&
6(++'
2QN++
2QN++
&0#
*GCVUJQEMIGPGUKP&TQUQRJKNCOGNCPQICUVGTCTGTCVGNKOKVGFFWTKPIGCTN[
GNQPICVKQP2TKQTVQJGCVUJQEM)#(EQCEVKXCVQTUCPFVJG)6(UCTGDQWPF
CV*URCPF2QN++KURTGUGPVCVVJGRTQOQVGTRTQZKOCNRCWUGUKVGYJGTGKV
UKVUKPCRQKUGFUVCVGTGCF[VQTGUWOGRTQFWEVKXGGNQPICVKQP*GCVUJQEM
KPFWEGUVTKOGTK\CVKQPQHVJGVTCPUETKRVKQPHCEVQT*5(YJKEJVJGPDKPFU
VQVJGRTQOQVGTQH*UR$KPFKPIQH*5(KUTGSWKTGFDWVKUPQVUWEKGPVVQ
TGETWKVVJGCEVKXCVKPIMKPCUG26'(DYJKEJRJQURJQT[NCVGUVJGKPJKDKVQT[
HCEVQTU0'.(CPF&5+(CUYGNNCUUGTKPGQHVJG%6&TGUWNVKPIKPTGNGCUGQH
2QN++KPVQRTQFWEVKXGVTCPUETKRVKQPGNQPICVKQP2#42ECVCN[UGUHQTOCVKQP
QH#&2TKDQUGRQN[OGTUCPFCNQPIYKVJ*5(CPF)#(KUTGSWKTGFHQT
PWENGQUQOGNQUUCV*URHQNNQYKPIJGCVUJQEM0WENGQUQOGNQUURTGEGGFU
VJGRCUUCIGQH2QN++CPFHCEKNKVCVGUIGPGCEVKXCVKQP
2QN++
2QN++
O40#
#VUQOGIGPGUCGT2QN++VTCPUETKDGUCUJQTVFKUVCPEGKPVQ
VJGIGPGKVRCWUGUCVCTGIKQPQH&0#MPQYPCUVJG
RTQOQVGTRTQZKOCNRCWUGUKVG2QN++KURTGXGPVGFHTQO
OQXKPIHQTYCTFHTQOVJKUTGIKQPD[KPJKDKVQT[HCEVQTUUWEJ
CU0'.(CPF&5+(
0QVG0'.(KUPQVRTGUGPVKP[GCUV
Transcription
DNA methylation
Chromatin modifying enzymes
DNA damage
&5+( 0'.(
2JQURJQT[NCVKQP
52
O40#
:2$
6$2
52
%6&
%6&
2TQOQVGT
RTQZKOCN
RCWUGF2QN++
6JG)CNIGPGUKP[GCUVJCXG
DGGPGZVGPUKXGN[UVWFKGFCPF
CTGKNNWUVTCVKXGQHVJGTQNG
QHCEVKXCVQTUKPKPKVKCVKPI
VTCPUETKRVKQP6JGRTGUGPEGQH
ICNCEVQUGTGNGCUGUVJGCEVKXCVQT
)CNHTQOKVUTGRTGUUQT)CN
YJKEJDGEQOGUUGSWGUVGTGFKP
VJGE[VQRNCUOD[)CN)CN
TGETWKVU5#)#HQNNQYGFD[
/GFKCVQTCPFVJGEJTQOCVKP
TGOQFGNNGT59+50(*KUVQPG
CEGV[NCVKQPD[5#)#UVKOWNCVGU
VJGTGOQFGNNKPIQHRTQOQVGT
PWENGQUQOGUD[59+50(
QTCPIG
PWENGUQOGKPFKECVGUOQXGOGPV
TGOQFGNNKPIGPJCPEGUVJG
MKPGVKEUQHCEVKXCVKQPCV)#.
#VQVJGTIGPGUEJTQOCVKP
TGOQFGNNKPIOC[DGC
TGSWKTGOGPVHQTCEVKXCVKQP
#V)#.5#)#CPF/GFKCVQT
YQTMVQIGVJGTVQTGETWKV2QN++
CPFVJGIGPGTCNVTCPUETKRVKQP
HCEVQTUVQVJGRTQOQVGTYJGTG
VJGRTGKPKVKCVKQPEQORNGZ
HQTOU+PVJKUGZCORNG
TGETWKVOGPVQH2QN++CPF
RTGKPKVKCVKQPEQORNGZHQTOCVKQP
CTGVJGTCVGNKOKVKPIUVGRUFWTKPI
VTCPUETKRVKQPCEVKXCVKQP
%&-
2JQURJQT[NCVKQP
#GTVJGRTGKPKVKCVKQPEQORNGZJCUHQTOGF%&-YKVJKP6(++*
RJQURJQT[NCVGUVJGUGTKPGRQUKVKQP
52YKVJKPVJGECTDQZ[VGTOKPCN
FQOCKP
%6&QHVJGNCTIGUVUWDWPKVQH2QN++#TQWPFVJGUCOGVKOGVJG
&0#JGNKECUG:2$WPYKPFUsDCUGUQH&0#CVVJGRTQOQVGTVQ
KPVTQFWEGCUKPINGUVTCPFGFVGORNCVGKPVQVJGCEVKXGUKVGQH2QN++
UGG
ENQUGWRCDQXG6TCPUETKRVKQPDGIKPUCU2QN++FKUUQEKCVGUHTQOOCP[QH
VJGIGPGTCNVTCPUETKRVKQPHCEVQTUENGCTUVJGRTQOQVGTCPFDGIKPUVQ
OCMG40#&WTKPIRTGKPKVKCVKQPEQORNGZHQTOCVKQPCPFRTQOQVGT
ENGCTCPEGUGXGTCNFKGTGPVJKUVQPGOQFKECVKQPUCTGFGRQUKVGFQP
PWENGQUQOGUCVVJGRTQOQVGTKPENWFKPI*-VTKOGVJ[NCVKQPCPF*$
OQPQWDKSWKV[NCVKQP
UGGUKFGRCPGN
5GSWGPVKCNJKUVQPGOQFKECVKQPUQEEWTCVRTQOQVGTU
*$WDKSWKV[NCVKQP
*-VTKOGVJ[NCVKQP
$WT
5GV
2+%
%1/2#55
$TG 4CF
2#(EQORNGZ
*KUVQPG*N[UKPG
*-
VTKOGVJ[NCVKQPKUCUUQEKCVGFYKVJ
CEVKXGVTCPUETKRVKQP+P[GCUV
VJKUOCTMKUFGRQUKVGFD[5GV
YKVJKP%1/2#55CPFTGSWKTGU
RTKQTWDKSWKV[NCVKQPQHJKUVQPG
*$D[4CFCPF$TG(QT
UKORNKEKV[VJGUGRTQVGKPUCTG
PQVUJQYPKPQVJGTRCPGNU
References
Abbreviations
Acknowledgements
Fuda, N. J., Ardehali, M. B. & Lis, J. T. Defining mechanisms that regulate RNA
polymerase II transcription in vivo. Nature 461, 186192 (2009) | Weake, V. M. &
Workman, J. L. Inducible gene expression: diverse regulatory mechanisms. Nature
Rev. Genet. 11, 426437 (2010) | Kornberg, R. D. The molecular basis of eukaryotic
transcription. Proc. Natl Acad. Sci. USA 104, 1295512961 (2007) | Orphanides, G.
& Reinberg, D. A unified theory of gene expression. Cell 108, 439451 (2002) |
Ptashne, M. & Gann, A. Transcriptional activation by recruitment. Nature 386,
569577 (1997) | Roeder, R. G. Transcriptional regulation and the role of diverse
coactivators in animal cells. FEBS Lett. 579, 909915 (2005)