Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II.
Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II.
复制标题
果蝇Kismet调节组蛋白H3赖氨酸27甲基化和RNA聚合酶II的早期延伸。
DOI：
10.1371/journal.pgen.1000217
复制
发表时间：
2008-10
期刊：
影响因子：
4.5
通讯作者：
Tamkun, John W.
中科院分区：
文献类型：
--
作者：
Srinivasan, Shrividhya;Dorighi, Kristel M.;Tamkun, John W.
Polycomb and trithorax group proteins regulate cellular pluripotency and differentiation by maintaining hereditable states of transcription. Many Polycomb and trithorax group proteins have been implicated in the covalent modification or remodeling of chromatin, but how they interact with each other and the general transcription machinery to regulate transcription is not well understood. The trithorax group protein Kismet-L (KIS-L) is a member of the CHD subfamily of chromatin-remodeling factors that plays a global role in transcription by RNA polymerase II (Pol II). Mutations in CHD7, the human counterpart of kis, are associated with CHARGE syndrome, a developmental disorder affecting multiple tissues and organs. To clarify how KIS-L activates gene expression and counteracts Polycomb group silencing, we characterized defects resulting from the loss of KIS-L function in Drosophila. These studies revealed that KIS-L acts downstream of P-TEFb recruitment to stimulate elongation by Pol II. The presence of two chromodomains in KIS-L suggested that its recruitment or function might be regulated by the methylation of histone H3 lysine 4 by the trithorax group proteins ASH1 and TRX. Although we observed significant overlap between the distributions of KIS-L, ASH1, and TRX on polytene chromosomes, KIS-L did not bind methylated histone tails in vitro, and loss of TRX or ASH1 function did not alter the association of KIS-L with chromatin. By contrast, loss of kis function led to a dramatic reduction in the levels of TRX and ASH1 associated with chromatin and was accompanied by increased histone H3 lysine 27 methylation—a modification required for Polycomb group repression. A similar increase in H3 lysine 27 methylation was observed in ash1 and trx mutant larvae. Our findings suggest that KIS-L promotes early elongation and counteracts Polycomb group repression by recruiting the ASH1 and TRX histone methyltransferases to chromatin. The transcription of eukaryotic genes involves a highly ordered series of events, including the recruitment of RNA polymerase to promoters, the production of the RNA transcript, and termination. These events are coordinated with changes in chromatin structure that allow regulatory proteins and RNA polymerase to access the DNA template. The recruitment of RNA polymerase II to promoters is rate-limiting for the expression of most eukaryotic genes. However, RNA polymerase often pauses or stalls a short distance downstream of promoters, providing an additional step at which transcription can be regulated. In this study, we present evidence suggesting that a chromatin-remodeling factor, KIS-L, activates transcription by counteracting promoter-proximal pausing in Drosophila. KIS-L also counteracts histone H3 lysine 27 methylation—a covalent modification of chromatin involved in hereditable gene silencing. Our findings provide a plausible explanation for the developmental abnormalities associated with CHARGE syndrome, a serious disorder resulting from mutations in the human counterpart of KIS-L.
登录
查看更多内容
影响因子：
64.5
作者：
Guenther, Matthew G.;Levine, Stuart S.;Young, Richard A.
通讯作者：
Young, Richard A.
DOI：
10.1073/pnas.85.21.8136
发表时间：
1988-11-01
影响因子：
11.1
作者：
KENNISON, JA;TAMKUN, JW
通讯作者：
TAMKUN, JW
影响因子：
11.4
作者：
CHINWALLA, V;JANE, EP;HARTE, PJ
通讯作者：
HARTE, PJ
影响因子：
64.5
作者：
Cosma, MP;Tanaka, TU;Nasmyth, K
通讯作者：
Nasmyth, K
DOI：
10.1139/o07-063
发表时间：
2007-08-01
期刊：
BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE
影响因子：
--
作者：
Hall, J. Adam;Georgel, Philippe T.
通讯作者：
Georgel, Philippe T.