наследование эпигенетических модификаций

2009
ÖÈÒÎËÎÃÈß
Ò î ì 51, ¹ 4
ÍÀÑËÅÄÎÂÀÍÈÅ ÝÏÈÃÅÍÅÒÈ×ÅÑÊÈÕ ÌÎÄÈÔÈÊÀÖÈÉ ÕÐÎÌÀÒÈÍÀ,
ÍÀÏÐÀÂËßÅÌÎÅ ÐÍÊ
© Í. Â. Òîìèëèí
Èíñòèòóò öèòîëîãèè ÐÀÍ, Ñàíêò-Ïåòåðáóðã; ýëåêòðîííûé àäðåñ: nvtom@mail.ru
Í. Â. Òîìèëèí
Ðàññìàòðèâàþòñÿ íîâûå ëèòåðàòóðíûå äàííûå î ìåõàíèçìå íàñëåäîâàíèÿ ðåïðåññèâíûõ ýïèãåíåòè÷åñêèõ ìîäèôèêàöèé õðîìàòèíà, ãèñòîíîâ è ÄÍÊ, êîòîðûå ñâèäåòåëüñòâóþò î òîì, ÷òî ýòè ìîäèôèêàöèè
íàïðàâëÿþòñÿ ÐÍÊ. ÐÍÊ ñ÷èòûâàåòñÿ ñ áîëüøèíñòâà ó÷àñòêîâ ãåíîìà, è òîãäà, êîãäà îíà ôîðìèðóåò äóïëåêñíûå ñòðóêòóðû çà ñ÷åò ïåðåêðûâàþùåéñÿ òðàíñêðèïöèè èëè çà ñ÷åò äîñòðàèâàíèÿ ÐÍÊ-çàâèñèìîé
ÐÍÊ-ïîëèìåðàçîé, îáðàçóåòñÿ ãåòåðîõðîìàòèí. Ìèòîòè÷åñêîå ôîñôîðèëèðîâàíèå Ser-10 â ãèñòîíå Í3
ñòèìóëèðóåò òðàíñêðèïöèþ ãåòåðîõðîìàòèíà è îáåñïå÷èâàåò åãî âîññòàíîâëåíèå â ñëåäóþùåì öèêëå ïóòåì ÐÍÊ-èíòåðôåðåíöèè.
Íàñëåäîâàíèå ýïèãåíåòè÷åñêèõ ìîäèôèêàöèé õðîìàòèíà, íàïðàâëÿåìîå ÐÍÊ
Ê ë þ ÷ å â û å ñ ë î â à: ýïèãåíåòèêà, ìîäèôèêàöèÿ ãèñòîíîâ, õðîìàòèí, ìåòèëèðîâàíèå ÄÍÊ.
Ãåíåòè÷åñêàÿ èíôîðìàöèÿ â æèâûõ îðãàíèçìàõ ïåðåäàåòñÿ â ðÿäó ïîêîëåíèé ñ ïîìîùüþ ïîëóêîíñåðâàòèâíîé
ìàòðè÷íîé ðåïëèêàöèè ÄÍÊ âî âðåìÿ ñèíòåòè÷åñêîé (S)
ôàçû êëåòî÷íîãî öèêëà. Êðîìå òîãî, ïðè êàæäîì äåëåíèè â äî÷åðíèå êëåòêè ïåðåäàåòñÿ áîëüøîé îáúåì ýïèãåíåòè÷åñêîé èíôîðìàöèè, ïðåæäå âñåãî èíôîðìàöèè îá
óðîâíå òðàíñêðèïöèîííîé àêòèâíîñòè êàæäîãî ãåíà. Ðåïëèêàöèÿ ÄÍÊ îñíîâàíà íà êîìïëåìåíòàðíûõ âçàèìîäåéñòâèÿõ íóêëåîòèäîâ è ñâîéñòâàõ ÄÍÊ-ïîëèìåðàç, îäíàêî îáùèé ìåõàíèçì íàñëåäîâàíèÿ ýïèãåíåòè÷åñêèõ
ìîäèôèêàöèé äî ïîñëåäíåãî âðåìåíè îñòàâàëñÿ íåèçâåñòíûì. Ïðåäïîëàãàëîñü, ÷òî òàêîå íàñëåäîâàíèå âîçìîæíî áëàãîäàðÿ ïàññèâíîé ïåðåäà÷å ïðè êëåòî÷íûõ äåëåíèÿõ êàêèõ-òî ðàñòâîðèìûõ ôàêòîðîâ íóêëåîïëàçìû è
öèòîïëàçìû, íàïðèìåð óíèêàëüíîãî íàáîðà áåëêîâûõ
êîìïëåêñîâ, ñïîñîáíûõ ðåãóëèðîâàòü òðàíñêðèïöèþ. Ýòè
êîìïëåêñû, îäíàêî, áûñòðî òåðÿþòñÿ ïðè äåëåíèÿõ, èõ íåîáõîäèìî âîññòàíàâëèâàòü ïóòåì ðåñèíòåçà è ñàìîñáîðêè, è îñòàåòñÿ íåÿñíûì, êàê òàêèå êîìïëåêñû ìîãóò
óçíàâàòü òå ìíîãî÷èñëåííûå ó÷àñòêè ãåíîìà, êîòîðûå
íóæíî ðåïðåññèðîâàòü èëè àêòèâèðîâàòü. Ðàíåå íà ðàñòåíèÿõ áûëî ïîêàçàíî, ÷òî íåêîòîðûå ýïèãåíåòè÷åñêèå
ìîäèôèêàöèè (ïàðàìóòàöèè) ïåðåäàþòñÿ íåìåíäåëåâñêèì
ñïîñîáîì â íåñêîëüêèõ ïîêîëåíèÿõ ÷åðåç êëåòêè çàðîäûøåâîãî ïóòè (Brink, 1958). Íåäàâíî ýòî ÿâëåíèå áûëî ïîäòâåðæäåíî íà ìûøàõ è óñòàíîâëåíî, ÷òî îíî îïîñðåäîâàíî ÐÍÊ (Rassoulzadegan et al., 2006). Áûëî òàêæå ïîêàçàíî, ÷òî äëÿ ïåðåäà÷è ïàðàìóòàöèé ó êóêóðóçû òðåáóåòñÿ
ÐÍÊ-çàâèñèìàÿ ÐÍÊ-ïîëèìåðàçà, ò. å. ðåïëèêàöèÿ ÐÍÊ
(Alleman et al., 2006). Òàêèì îáðàçîì, íàñëåäîâàíèå ýïèãåíåòè÷åñêèõ ìîäèôèêàöèé â ðÿäó ïîêîëåíèé ó ðàñòåíèé è
æèâîòíûõ âîçìîæíî ÷åðåç ÐÍÊ, à íå ÄÍÊ èëè áåëîê (Cuzin et al., 2008).  îòëè÷èå îò áåëêîâûõ êîìïëåêñîâ äàæå
êîðîòêèå ÐÍÊ (äëèíîé 16—30 íóêëåîòèäîâ) ñïîñîáíû óçíàâàòü çà ñ÷åò êîìïëåìåíòàðíîñòè ëþáûå ñïåöèôè÷åñêèå
ó÷àñòè ãåíîìà è ìîãóò îáåñïå÷èâàòü èõ àäðåñíóþ ðåïðåññèþ.
Íåòðàíñëèðóåìàÿ äëèííàÿ (15 êá) ÐÍÊ, ó÷àñòâóþùàÿ
â ïîääåðæàíèè íåàêòèâíîé X-õðîìîñîìû (Xist RNA),
áûëà èäåíòèôèöèðîâàíà ó ìûøåé â 1991 ã. (Brockdorff
et al., 1991, 1992). Ãåí ýòîé ÐÍÊ íàõîäèòñÿ â ëîêóñå íà
X-õðîìîñîìå (Xic), îò êîòîðîãî ðàñïðîñòðàíÿåòñÿ âîëíà
ðåïðåññèè òðàíñêðèïöèè â èíàêòèâèðóþùåéñÿ êîïèè
X-õðîìîñîìû â ðàííåì ýìáðèîãåíåçå ó ñàìîê. Ýòà âîëíà
âîçíèêàåò áëàãîäàðÿ ïîñòåïåííîìó íàêîïëåíèþ Xist RNA
ïî îáå ñòîðîíû îò Xic, çàòåì íåàêòèâíîñòü îäíîé X-õðîìîñîìû ïîääåðæèâàåòñÿ êëîíàëüíî âî âñåõ ïîñëåäóþùèõ
äåëåíèÿõ ñîìàòè÷åñêèõ êëåòîê (Heard, 2005). Äîïîëíèòåëüíàÿ Xist ÐÍÊ, íåîáõîäèìàÿ äëÿ ïîääåðæàíèÿ ðåïðåññèè, ñèíòåçèðóåòñÿ, î÷åâèäíî, ïðè êàæäîì äåëåíèè ñîìàòè÷åñêèõ êëåòîê.  2008 ã. ïîêàçàíî, ÷òî âûêëþ÷åíèå àïïàðàòà èíòåðôåðåíöèè ÐÍÊ (èíàêòèâàöèÿ ãåíà DICER, ñì.
íèæå) ïîäàâëÿåò ñèíòåç Xist ÐÍÊ íà àêòèâíîé X-õðîìîñîìå è íàêîïëåíèå Xist ÐÍÊ íà íåàêòèâíîé X (Ogawa et al.,
2008).
Ðîëü êîðîòêîé (ìàëîé) ÐÍÊ â ðåãóëÿöèè ãåííîé ýêñïðåññèè áûëà âïåðâûå ïîêàçàíà íà ìîäåëè ãåíà Lin-4 Caenorhabditis elegans â ëàáîðàòîðèè Â. Àìáðîñà â 1993 ã.
(Lee et al., 1993). Íàïðàâëÿåìîå ÐÍÊ ìåòèëèðîâàíèå ÄÍÊ
áûëî îòêðûòî â 1994 ã. íà ðàñòåíèÿõ, èíôèöèðîâàííûõ
âèðîèäàìè (Wassenegger et al., 1994). Ñïåöèôè÷åñêîå èíãèáèðîâàíèå òðàíñêðèïöèè èñêóññòâåííî ââåäåííîé äóïëåêñíîé ÐÍÊ áûëî âïåðâûå îáíàðóæåíî â îïûòàõ íà
C. elegans â 1998 ã. (Fire et al., 1998), ýòà ðàáîòà áûëà íåäàâíî óäîñòîåíà Íîáåëåâñêîé ïðåìèè. Çàòåì ïîñëåäîâàëè
ìíîãî÷èñëåííûå ðàáîòû íà ðàçëè÷íûõ îáúåêòàõ, êîòîðûå
âûÿâèëè ñïåöèôè÷åñêèå êîíñåðâàòèâíûå ãåíû è áåëêîâûå êîìïëåêñû, íåîáõîäèìûå äëÿ ïðîöåññèíãà äóïëåêñíîé ÐÍÊ è îáðàçîâàíèÿ ìàëûõ èíòåðôåðèðóþùèõ ÐÍÊ
(siRNA): ãåíû DICER, ARGONAUTE, à òàêæå êîìïëåêñû
RISC (RNA Induced Silencing Complex) è RITS (RNA Induced Transcription Silencing) (ñì. îáçîðû: Bernstein et al.,
2001; Hannon, 2002; Baulcombe, 2004; Lippman, Martienssen, 2004). Êîìïëåêñû RISC âûçûâàþò ðàñïàä mÐÍÊ èëè
291
292
Í. Â. Òîìèëèí
òîðìîæåíèå åå òðàíñëÿöèè, à êîìïëåêñû RITS íåîáõîäèìû äëÿ ïîäàâëåíèÿ òðàíñêðèïöèè è ïîääåðæàíèÿ ãåòåðîõðîìàòèíà (Lippman, Martienssen, 2004; Matzke, Matzke,
2004). Íà äðîçîôèëå èíäóöèðóåìîå äóïëåêñíîé ÐÍÊ ãëóøåíèå òðàíñêðèïöèè òàíäåìíûõ ïîâòîðîâ è òðàíñïîçîíîâ
â êëåòêàõ çàðîäûøåâîãî ïóòè áûëî îòêðûòî â ëàáîðàòîðèè Â. À. Ãâîçäåâà (Aravin et al., 2001). Äàëüíåéøåå èññëåäîâàíèå ýòîãî ÿâëåíèÿ ïîêàçàëî, ÷òî îíî çàâèñèò îò
ìàëûõ ÐÍÊ, ñâÿçûâàþùèõñÿ ñ áåëêîì PIWI (ðàçíîâèäíîñòü áåëêà ARGONAUTE) è åãî ãîìîëîãàìè â êëåòêàõ
ìëåêîïèòàþùèõ MILI è MIWI (Aravin et al., 2004, 2007a,
2007b). Ýòè æå áåëêè íàïðàâëÿþò ìåòèëèðîâàíèå ÄÍÊ
ðåòðîòðàíñïîçîíîâ â ìóæñêèõ ãîíàäàõ ó ìûøåé (Kuramochi-Miyazawa et al., 2008), íî îíè, ïî-âèäèìîìó, íå ðàáîòàþò â ñîìàòè÷åñêèõ êëåòêàõ æèâîòíûõ, êîòîðûå èñïîëüçóþò äðóãîé ïóòü ÐÍÊ-èíòåðôåðåíöèè, çàâèñèìûé îò
áåëêà DICER (Obbard, Finnegan, 2008). ÐÍÊ, âçàèìîäåéñòâóþùèå ñ áåëêîì PIWI, ñ÷èòûâàþòñÿ ñ îïðåäåëåííûõ
êëàñòåðîâ â ãåíîìå, ñîäåðæàùèõ ðåòðîòðàíñïîçîíû, è çàòåì ïðîöåññèðóþòñÿ â îäíîòÿæåâóþ ÐÍÊ äëèíîé 23—29
íóêëåîòèäîâ, íî íåÿñíî, ìîæåò ëè ñ ïîìîùüþ PIWI ïðîöåññèðîâàòüñÿ ëþáàÿ äóïëåêñíàÿ ÐÍÊ. Ðàçëè÷íûå ïóòè è
ìåõàíèçìû ÐÍÊ-èíòåðôåðåíöèè ðàññìîòðåíû íåäàâíî â
îáçîðå Ðÿçàíñêîãî è Ãâîçäåâà (Ryazansky, Gvozdev, 2007).
Äîëãîå âðåìÿ ñ÷èòàëîñü, ÷òî ýñïðåññèðóåòñÿ ëèøü
î÷åíü íåáîëüøàÿ äîëÿ (<5 %) ãåíîìîâ âûñøèõ ýóêàðèîò,
ñîîòâåòñòâóþùàÿ êîäèðóþùèì ïîñëåäîâàòåëüíîñòÿì
áåëêîâ è íåêîòîðûõ âàæíûõ ÐÍÊ, îäíàêî â ïîñëåäíèå
ãîäû âûÿñíåíî, ÷òî â êëåòêàõ æèâîòíûõ òðàíñêðèáèðóåòñÿ íå ìåíåå 70 % ãåíîìà, ïðè÷åì èìååòñÿ î÷åíü ìíîãî
òðàíñêðèïòîâ ñ îáåèõ êîìïëåìåíòàðíûõ íèòåé (Carninci
et al., 2005; Kapranov et al., 2007). Èíòåíñèâíîñòü òðàíñêðèïöèè ðàçíûõ ó÷àñòêîâ ãåíîìà, êîíå÷íî, ñóùåñòâåííî
âàðüèðóåò, íî ïðè íåêîòîðûõ óñëîâèÿõ òðàíñêðèáèðóåòñÿ
äàæå êîìïàêòíûé öåíòðîìåðíûé õðîìàòèí. Ïîñêîëüêó
ãëàâíûì ïåðâè÷íûì ïðîäóêòîì ãåíîìîâ ÿâëÿåòñÿ ÐÍÊ,
äëÿ áèîëîãèè ðàçâèòèÿ ïðåäëàãàåòñÿ íîâàÿ ïàðàäèãìà, ñîñòîÿùàÿ â òîì, ÷òî íåêîäèðóþùàÿ ÐÍÊ èìååò ðåãóëÿòîðíûå ôóíêöèè (Mattick, 2007) è ÷òî ÐÍÊ êîíòðîëèðóåò
ýïèãåíåòè÷åñêèå ìîäèôèêàöèè ñîìàòè÷åñêèõ êëåòîê, íà
êîòîðûõ îñíîâàíû âñå îíòîãåíåçû ìíîãîêëåòî÷íûõ îðãàíèçìîâ. Çíà÷èòåëüíóþ ÷àñòü «íåêîäèðóþùåé» ÄÍÊ ñîñòàâëÿþò ðåòðîýëåìåíòû, êîòîðûå èãðàþò âàæíóþ ðîëü â
ðåãóëÿöèè ýêñïðåññèè ãåíîâ (Goodier, Kazazian, 2008; Tomilin, 2008) è, òàêèì îáðàçîì, ìîãóò ñóùåñòâåííî âëèÿòü
íà ñîñòàâ êîäèðóþùèõ è íåêîäèðóþùèõ ÐÍÊ â êëåòêå.
 ñîìàòè÷åñêèõ êëåòêàõ â õðîìàòèíå èìåþòñÿ êàê àêòèâíî òðàíñêðèáèðóþùèåñÿ äîìåíû (ñîñòàâëÿþùèå ýóõðîìàòèí), òàê è íåàêòèâíûå äîìåíû (ãåòåðîõðîìàòèí), â
êîòîðûõ òðàíñêðèïöèÿ ïîäàâëåíà, ïðè÷åì õàðàêòåðíàÿ
äëÿ äàííîãî òèïà êëåòîê ìîçàèêà àêòèâíûõ è íåàêòèâíûõ
äîìåíîâ ïåðåäàåòñÿ âî âðåìÿ êëåòî÷íûõ äåëåíèé.
 òðàíñêðèïöèîííî íåàêòèâíûõ äîìåíàõ ÄÍÊ, êàê ïðàâèëî, ìåòèëèðîâàíà ïî öèòîçèíó â ïàðàõ CpG (Vaniushin,
2006), à ãèñòîí H3 â õðîìàòèíå ìåòèëèðîâàí ïî îñòàòêó
Lys-9 èëè Lys-27. Ïðè äåëåíèÿõ ñîõðàíÿåòñÿ êàê êàðòèíà
ìåòèëèðîâàíèÿ ÄÍÊ, òàê è êàðòèíà îáðàòèìûõ ïîñòòðàíñëÿöèîííûõ ìîäèôèêàöèé ãèñòîíîâ (Bradbury, 1992), ñîñòàâëÿþùàÿ òàê íàçûâàåìûé ãèñòîíîâûé êîä (Strahl, Allis, 2000; Jenuwein, Allis, 2001). Ñ÷èòàåòñÿ, ÷òî êàðòèíà
ìåòèëèðîâàíèÿ ÄÍÊ âîñïðîèçâîäèòñÿ áëàãîäàðÿ äîïîëíèòåëüíîìó ìåòèëèðîâàíèþ âî âðåìÿ S-ôàçû ïîëóìåòèëèðîâàííîé ÄÍÊ-ñïåöèôè÷åñêîé «ïîääåðæèâàþùåé»
ÄÍÊ-ìåòèëàçîé òèïà DNMT1, êîòîðàÿ èìååòñÿ â ñîìàòè÷åñêèõ è ïîëîâûõ êëåòêàõ (Bestor, 2000). Ýòà ìåòèëàçà,
îäíàêî, ìîæåò ìîäèôèöèðîâàòü è íåìåòèëèðîâàííóþ
ÄÍÊ è èìååò ëèøü íåáîëüøîå ïðåäïî÷òåíèå ê ïîëóìåòèëèðîâàííîé ÄÍÊ (Yoder et al., 1997). Îñòàåòñÿ íåÿñíûì,
ïî÷åìó DNMT1 íå ìîäèôèöèðóåò â ñîìàòè÷åñêèõ êëåòêàõ òðàíñêðèïöèîííî àêòèâíûå äîìåíû õðîìàòèíà
de novo. Âåðîÿòíî, äîïîëíèòåëüíûå ðåãóëÿòîðíûå ôàêòîðû, à òàêæå ñòðóêòóðà õðîìàòèíà èãðàþò ãëàâíóþ ðîëü â
îïðåäåëåíèè ìèøåíåé äëÿ DNMT1, äàæå ïîëóìåòèëèðîâàííîé ÄÍÊ. Òàêèì ôàêòîðîì ìîæåò áûòü, íàïðèìåð, áåëîê UHRF 1, êîòîðûé «âûâîðà÷èâàåò» 5-ìåòèëöèòîçèí èç
äóïëåêñíîé ïîëóìåòèëèðîâàííîé ÄÍÊ (Arita et al., 2008;
Avvakumov et al., 2008; Hashimoto et al., 2008). Ïðåäïîëàãàåòñÿ, ÷òî âàæíóþ ðîëü ñðåäè óêàçàííûõ ôàêòîðîâ èãðàþò òàêæå ìîäèôèêàöèè õðîìàòèíà, íàïðàâëÿåìûå ÐÍÊ
(Kloc, Martienssen, 2008).
×òî êàñàåòñÿ ìåõàíèçìà âîñïðîèçâåäåíèÿ êàðòèíû
ìîäèôèêàöèé ãèñòîíîâ, òî ðàññìàòðèâàþòñÿ äâå ãèïîòåçû. Ñîãëàñíî ïåðâîé èç íèõ, ìîäèôèêàöèè ãèñòîíîâ íåïîñðåäñòâåííî íàïðàâëÿþòñÿ ìåòèëèðîâàíèåì ÄÍÊ ïóòåì
ïðèâëå÷åíèÿ ãèñòîíìîäèôèöèðóþùèõ ôåðìåíòîâ. Ðåïðåññèâíîå ìåòèëèðîâàíèå ãèñòîíà H3 ïî Lys-9 âîñïðîèçâîäèòñÿ ïîñëå ïîääåðæèâàþùåãî CpG-ìåòèëèðîâàíèÿ
ÄÍÊ ñðàçó ïîñëå åå ðåïëèêàöèè. Ýòî ïðîèñõîäèò ñ ïîìîùüþ ìåòèë-CpG-ñâÿçûâàþùåãî áåëêà MBD1, êîòîðûé
ïðèâëåêàåò â ñàéòû ðåïëèêàöèè ãèñòîíìåòèëàçó SETDB1
(Sarraf, Stancheva, 2004), à òàêæå çà ñ÷åò ñïåöèôè÷åñêèõ
áåëîê-áåëêîâûõ âçàèìîäåéñòâèé êîìïëåêñà PCNA—
DNMT1 ñ ãèñòîíìåòèëàçîé G9a è ãèñòîíäåàöåòèëàçîé
HDAC2, à òàêæå âçàèìîäåéñòâèé MBD1—HP1 ñ ãèñòîíìåòèëàçîé Suv39h1 (Groth et al., 2007). Ïðåäïîëàãàåòñÿ,
÷òî âûñîêàÿ êîíöåíòðàöèÿ â ðåïëèêàòèâíûõ ôîêóñàõ óêàçàííûõ ìåòèëàç àâòîìàòè÷åñêè âåäåò ê ìåòèëèðîâàíèþ
Lys-9 â ãèñòîíå H3 (H3K9) è äåàöåòèëèðîâàíèþ äðóãèõ
ãèñòîíîâ è ýòîò ïðîöåññ íàïðàâëÿåòñÿ ïîääåðæèâàþùèì
ìåòèëèðîâàíèåì ÄÍÊ. MBD1 âçàèìîäåéñòâóåò òàêæå ñ
áåëêàìè Ring1b è hPc2 ðåïðåññèâíîãî êîìïëåêñà Polycomb (Sakamoto et al., 2007) è ìîæåò ïîýòîìó íàïðàâëÿòü
ìåòèëèðîâàíèå ãèñòîíà H3 ïî Lys-27 ñ ïîìîùüþ ãèñòîíìåòèëàçû EZH2, êîòîðàÿ ÿâëÿåòñÿ ñóáúåäèíèöåé óêàçàííîãî êîìïëåêñà. Èçëîæåííàÿ ãèïîòåçà, îäíàêî, íå ñîãëàñóåòñÿ ñ äàííûìè, ïîëó÷åííûìè íà ðàñòåíèÿõ è ôèëàìåíòîçíûõ ãðèáàõ, î òîì, ÷òî ìåòèëèðîâàíèå ÄÍÊ
íàïðàâëÿåòñÿ ìåòèëèðîâàíèåì ãèñòîíîâ (Jackson et al.,
2002; Tamaru et al., 2003). Ó ìûøåé èíàêòèâàöèÿ ãåíà ãèñòîíìåòèëòðàíñôåðàçû Suv39h, êîòîðàÿ ìåòèëèðóåò H3K9,
ïîíèæàåò ìåòèëèðîâàíèå ïðèöåíòðîìåðíûõ ñàòåëëèòíûõ
ÄÍÊ (Lehnertz et al., 2003). Âî âðåìÿ ýïèãåíåòè÷åñêîé
èíàêòèâàöèè ãåíà îïóõîëåâîãî ñóïðåññîðà RASSF1A â
êëåòêàõ ÷åëîâåêà â ïðîìîòîðå ýòîãî ãåíà âíà÷àëå ïðîèñõîäèò ìåòèëèðîâàíèå H3K9, à çàòåì óæå ìåòèëèðîâàíèå
ÄÍÊ (Strunnikova et al., 2005). Ïî ïîñëåäíèì äàííûì, ïîëó÷åííûì íà ýìáðèîíàëüíûõ ñòâîëîâûõ êëåòêàõ ìëåêîïèòàþùèõ, ìåòèëèðîâàíèå H3K9 ìåòèëàçîé G9a è ìåòèëèðîâàíèå ÄÍÊ ïðîèñõîäèò íåçàâèñèìî äðóã îò äðóãà
(Dong et al., 2008; Tachibana et al., 2008). Êðîìå òîãî, â íåêîòîðûõ ãåíîìàõ ïîçâîíî÷íûõ èìåþòñÿ äîâîëüíî ïðîòÿæåííûå ðàéîíû íåêîäèðóþùåé ÄÍÊ, íå ñîäåðæàùèå ïàð
CpG, êîòîðûå íå ìîãóò áûòü ìåòèëèðîâàíû âîîáùå.
Ê íèì îòíîñèòñÿ, íàïðèìåð, òåëîìåðíûé ãåòåðîõðîìàòèí,
ñîñòîÿùèé èç òàíäåìíûõ ïîâòîðîâ (TTAGGG)n (Tomilin,
2008). Òàêèì îáðàçîì, ìåòèëèðîâàíèå ÄÍÊ íå ìîæåò íàïðàâëÿòü ýïèãåíåòè÷åñêèå ìîäèôèêàöèè ãèñòîíîâ.
Âòîðàÿ ãèïîòåçà îòíîñèòåëüíî ìåõàíèçìà âîñïðîèçâåäåíèÿ êàðòèíû ðåïðåññèâíûõ ìîäèôèêàöèé ãèñòîíîâ âî
âðåìÿ êëåòî÷íûõ äåëåíèé ñîñòîèò â òîì, ÷òî ìåòèëèðîâà-
Íàñëåäîâàíèå ýïèãåíåòè÷åñêèõ ìîäèôèêàöèé õðîìàòèíà, íàïðàâëÿåìîå ÐÍÊ
293
Îáðàçîâàíèå ãåòåðîõðîìàòèíà áëàãîäàðÿ ïåðåêðûâàþùåéñÿ òðàíñêðèïöèè.
íèå ãèñòîíà H3 ïî ëèçèíó-9 íàïðàâëÿåòñÿ òðàíñêðèïöèåé
è siÐÍÊ. Áîëüøàÿ ðîëü ìàëûõ ÐÍÊ â ïîääåðæàíèè ãåòåðîõðîìàòèíà â äðîææàõ Schizosaccharomyces pombe áûëà
óñòàíîâëåíà íåñêîëüêî ëåò íàçàä (Volpe et al., 2002; Cam
et al., 2005; Martienssen et al., 2005), îäíàêî îñòàâàëîñü íåÿñíûì, êàê ðåãóëèðóåòñÿ òðàíñêðèïöèÿ ãåòåðîõðîìàòèíà,
íåîáõîäèìàÿ äëÿ îáðàçîâàíèÿ ìàëûõ ÐÍÊ, â êëåòî÷íîì
öèêëå.  2008 ã. îïóáëèêîâàíû äâå ñòàòüè, ãäå ýòîò âîïðîñ ïðîÿñíÿåòñÿ è ïðåäëàãàåòñÿ ìîäåëü íàñëåäîâàíèÿ ðåïðåññèâíûõ ìîäèôèêàöèé ãåòåðîõðîìàòèíà ïðè êëåòî÷íûõ äåëåíèÿõ äðîææåé S. pombe ñ ïîìîùüþ siÐÍÊ (Chen
et al., 2008; Kloc et al., 2008). Êëþ÷åâîå ñîáûòèå ïðîèñõîäèò â ìèòîçå ïóòåì ôîñôîðèëèðîâàíèÿ Ser-10 â ãèñòîíå
H3, ÷òî ïðèâîäèò ê ýëèìèíàöèè ãåòåðîõðîìàòèíîâîãî
áåëêà Swi6 (HP1) è àêòèâàöèè òðàíñêðèïöèè â ôàçàõ G1 è
ðàííåé S. Òðàíñêðèïòû ãåòåðîõðîìàòèíà íàêàïëèâàþòñÿ
â S-ôàçå è ïðåâðàùàþòñÿ â ñïåöèôè÷åñêèå siÐÍÊ-êîìïëåêñû (RITS-êîìïëåêñû: RNA Induced Transcription Silencing), êîòîðûå èíäóöèðóþò äîïîëíèòåëüíîå ìåòèëèðîâàíèå Lys-9 â ãèñòîíå H3 (ïîñëå ðåïëèêàöèè) è ñâÿçûâàíèå
áåëêà Swi6, ïîëíîñòüþ âîññòàíàâëèâàÿ òåì ñàìûì ãåòåðîõðîìàòèí â íîâîì öèêëå. Òàêèì îáðàçîì, ó S. pombe ãåòåðîõðîìàòèí ÷àñòè÷íî ðàçðóøàåòñÿ è âîññòàíàâëèâàåòñÿ
ïðè êàæäîì êëåòî÷íîì äåëåíèè ñ ïîìîùüþ ÐÍÊ-èíòåðôåðåíöèè. Ýòà ñõåìà ðàññìàòðèâàåòñÿ êàê ìîäåëü âîññòàíîâëåíèÿ ìîäèôèêàöèé ãèñòîíîâ â êëåòî÷íîì öèêëå, êîòîðûå íàïðàâëÿþò îáðàçîâàíèå ãåòåðîõðîìàòèíà (Thon,
2008), è äàæå êàê îáùàÿ ìîäåëü ýïèãåíåòè÷åñêîãî íàñëåäîâàíèÿ ó ýóêàðèîò, íàïðàâëÿåìîãî ÐÍÊ-èíòåðôåðåíöèåé
(Kloc, Martienssen, 2008). Íàñêîëüêî îïðàâäàííà òàêàÿ
òî÷êà çðåíèÿ?
Ìîæíî ñ÷èòàòü, ÷òî ôîñôîðèëèðîâàíèå ãèñòîíà H3 è
ýëèìèíàöèÿ â ìèòîçå íå ÿâëÿþòñÿ ñïåöèôè÷åñêèìè äëÿ
öåíòðîìåðíîãî ãåòåðîõðîìàòèíà S. pombe: ïîêàçàíî, ÷òî
ìèòîòè÷åñêàÿ ýëèìèíàöèÿ âñåõ òðåõ ôîðì áåëêà HP1 (àëüôà, áåòà è ãàììà) ïðîèñõîäèò è â êëåòêàõ ìûøåé, ïðè÷åì
âî âðåìÿ ìèòîçà â õðîìîñîìàõ îñòàåòñÿ òðèìåòèëèðîâàííûé H3K9, ñîõðàíÿþùèé ðåïðåññîðíóþ ìàðêèðîâêó ãåòåðîõðîìàòèíà (Fischle et al., 2005; Hirota et al., 2005) è, âåðîÿòíî, îòâåòñòâåííûé çà èçâåñòíûå Ñ-áàíäû â ìèòîòè÷åñêèõ õðîìîñîìàõ.  êëåòêàõ ìëåêîïèòàþùèõ ïèê
òðàíñêðèïöèè ïåðèöåíòðè÷åñêîãî ãåòåðîõðîìàòèíà îáíàðóæåí â ðàííåé S-ôàçå êëåòî÷íîãî öèêëà, îäíàêî áåëîê
HP1 îñòàåòñÿ â ýòîò ïåðèîä ñâÿçàííûì ñ ãåòåðîõðîìàòèíîì (Lu, Gilbert, 2008). Ìûøèíûé ãåòåðîõðîìàòèí òðàíñêðèáèðóåòñÿ è â ìèòîçå, êîãäà HP1 óäàëÿåòñÿ áëàãîäàðÿ
ôîñôîðèëèðîâàíèþ H3-Ser-10 (Fischle et al., 2005), íî êîðîòêèå ÐÍÊ, êîìïëåìåíòàðíûå ãåòåðîõðîìàòèíîâûì ïîâòîðàì, à òàêæå RITS-êîìïëåêñû ïîêà íå èäåíòèôèöèðîâàíû. Òðàíñêðèïöèÿ ãåòåðîõðîìàòèíà ïðîèñõîäèò âî
âðåìÿ G1- è ðàííåé S-ôàçû, íî îáðàçîâàíèå ñïåöèôè÷åñêèõ siÐÍÊ çàâèñèò îò òîãî, ôîðìèðóåòñÿ ëè äóïëåêñíàÿ
ÐÍÊ, íåîáõîäèìàÿ äëÿ ñîçðåâàíèÿ êîìïëåêñîâ RITS.
Ôîðìèðîâàíèå òàêîé ÐÍÊ âîçìîæíî ëèáî ïðè íàëè÷èè
â ÐÍÊ èíâåðèðîâàííûõ ïîâòîðîâ, ëèáî ïðè âñòðå÷íîé
òðàíñêðèïöèè îáåèõ êîìïëåìåíòàðíûõ íèòåé, ëèáî ïóòåì
äîñòðàèâàíèÿ âòîðîé êîìïëåìåíòàðíîé íèòè ÐÍÊ ñ ïîìîùüþ êîìïëåêñà, ñîäåðæàùåãî ÐÍÊ-çàâèñèìóþ ÐÍÊïîëèìåðàçó (RDRC). Ó äðîææåé S. pombe è ó ðàñòåíèé òàêàÿ ÐÍÊ-ïîëèìåðàçà èìååòñÿ, îíà íåîáõîäèìà äëÿ îáðàçîâàíèÿ öåíòðîìåðíîãî ãåòåðîõðîìàòèíà (Iida et al., 2008),
îäíàêî â êëåòêàõ æèâîòíûõ RDRC íå îáíàðóæåíà è äóïëåêñíûå ÐÍÊ ìîãóò ôîðìèðîâàòüñÿ, ïî-âèäèìîìó, òîëüêî
çà ñ÷åò ïåðåêðûâàþùèõñÿ òðàíñêðèïòîâ èëè ïðè íàëè÷èè
â ýòèõ òðàíñêðèïòàõ èíâåðòèðîâàííûõ ïîâòîðîâ. Î÷åâèäíî, ÷òî âûñîêîàêòèâíûå ãåíû, â êîòîðûõ òðàíñêðèáèðóåòñÿ òîëüêî îäíà íèòü ÄÍÊ, íå ìîãóò ïðîäóöèðîâàòü äóïëåêñíûå ÐÍÊ, îäíàêî â äîìåíàõ, â êîòîðûõ èíòåí-
294
Í. Â. Òîìèëèí
ñèâíîñòü ñìûñëîâîé òðàíñêðèïöèè ñîïîñòàâèìà ñ
èíòåíñèâíîñòüþ àíòèñìûñëîâîé òðàíñêðèïöèè, äóïëåêñíûå ÐÍÊ ìîãóò âîçíèêàòü. Äóïëåêñíàÿ ÐÍÊ, îáðàçîâàíèå
êîìïëåêñîâ RITS è íåöåíòðîìåðíîãî ãåòåðîõðîìàòèíà â
ôàçå G1 öèêëà ïóòåì ÐÍÊ-èíòåðôåðåíöèè áûëè îáíàðóæåíû ïðè àíàëèçå êîíâåðãåíòíîé òðàíñêðèïöèè ñîñåäíèõ
ãåíîâ ó S. pombe (Gullerova, Proudfoot, 2008). Ïî-âèäèìîìó, íå òîëüêî öåíòðîìåðíûå òðàíñêðèïòû, íî è äðóãèå
òðàíñêðèïòû, ñïîñîáíûå îáðàçîâûâàòü äóïëåêñíóþ ÐÍÊ,
ìîãóò èíäóöèðîâàòü ÐÍÊ-èíòåðôåðåíöèþ ó S. pombe.
Ó æèâîòíûõ èäåíòèôèöèðîâàíî ìíîãî êîíâåðãåíòíûõ êîäèðóþùèõ è íåêîäèðóþùèõ òðàíñêðèïòîâ, êîòîðûå ìîãóò ôîðìèðîâàòü äóïëåêñíóþ ÐÍÊ è êîìïëåêñû
RITS. Â áàçå äàííûõ ANTICODE (ïî àäðåñó: www.anticode.org) èìååòñÿ áîëåå 10 000 ïàð ïåðåêðûâàþùèõñÿ
òðàíñêðèïòîâ èç êëåòîê ÷åëîâåêà. Ñîîòâåòñòâóþùèå
siÐÍÊ ìîãóò äàâàòü ñóùåñòâåííûé âêëàä â ýïèãåíåòè÷åñêóþ ðåãóëÿöèþ ãåííîé ýêñïðåññèè è âîñïðîèçâåäåíèå
êàðòèíû ýêñïðåññèè ïðè êëåòî÷íûõ äåëåíèÿõ.  2008 ã.
áûë èäåíòèôèöèðîâàí íîâûé êëàññ ýíäîãåííûõ siÐÍÊ,
ïîäàâëÿþùèõ òðàíñêðèïöèþ òðàíñïîçîíîâ â ñîìàòè÷åñêèõ êëåòêàõ äðîçîôèëû (Obbard, Finnegan, 2008). Ýòè
3S-ìåòèëèðîâàííûå ÐÍÊ äëèíîé 21 íóêëåîòèä îêàçàëèñü
êîìïëåìåíòàðíûìè òðàíñïîçîíàìè è íåêîòîðûì äðóãèì
ëîêóñàì, âêëþ÷àÿ åñòåñòâåííûå àíòèñìûñëîâûå òðàíñêðèïòû (Okamura et al., 2008), à òàêæå äëèííûå èíâåðòèðîâàííûå (fold-back) ïîñëåäîâàòåëüíîñòè, à èõ ïðîöåññèíã çàâèñåë îò ïðîäóêòîâ ãåíîâ Dicer 2 (Dcr2) è Argonaute 2 (Ago2).  ýòèõ ìàëûõ ÐÍÊ îáíàðóæåíû ïðèçíàêè
ðåäàêòèðîâàíèÿ (Chung et al., 2008; Kawamura et al., 2008)
è ñäåëàíî ïðåäïîëîæåíèå î òîì, ÷òî îíè íóæíû äëÿ ïîääåðæàíèÿ ãåòåðîõðîìàòèíà â ñîìàòè÷åñêèõ êëåòêàõ (Kawamura et al., 2008). Ïîêà íåÿñíî, ðàáîòàþò ëè àíàëîãè÷íûå ìàëûå ÐÍÊ â ñîìàòè÷åñêèõ êëåòêàõ ìëåêîïèòàþùèõ, îäíàêî åñòü óêàçàíèÿ íà òî, ÷òî ÐÍÊ,
ñ÷èòûâàþùàÿñÿ ñ íåêîòîðûõ ðåòðîýëåìåíòîâ ìëåêîïèòàþùèõ, íàïðèìåð èíâåðòèðîâàííûõ Alu-ïîâòîðîâ, ëîêàëèçîâàííûõ â 3S-UTR-ðàéîíàõ èÐÍÊ, ïîäâåðãàåòñÿ èíòåíñèâíîìó ðåäàêòèðîâàíèþ, ñîñòîÿùåìó â ôåðìåíòàòèâíîì ïðåâðàùåíèè àäåíîçèíà â èíîçèí, êîòîðûé ñïàðèâàåòñÿ, êàê
ãóàíîçèí (Levanon et al., 2005). Ôóíêöèîíàëüíîå çíà÷åíèå
òàêîãî ðåäàêòèðîâàíèÿ Alu-ÐÍÊ íå óñòàíîâëåíî, îäíàêî
èíâåðòèðîâàííûå Alu â èíòðîíàõ ãåíîâ ðåäàêòèðóþòñÿ è
âëèÿþò íà àëüòåðíàòèâíûé ñïëàéñèíã èÐÍÊ (Lev-Maor
et al., 2008). Ñëåäîâàòåëüíî, îíè ìîãóò êîìïëåìåíòàðíî
âçàèìîäåéñòâîâàòü â ñîñòàâå ïðå-èÐÍÊ è ðåãóëèðîâàòü
àëüòåðíàòèâíûé ñïëàéñèíã. Ðåäàêòèðîâàíèå ÐÍÊ è ïîäàâëåíèå ãåííîé ýêñïðåññèè ïóòåì ÐÍÊ èíòåðôåðåíöèè
êàê-òî ñâÿçàíû (Nishikura, 2006), îäíàêî íåÿñíî, ìîãóò ëè
siÐÍÊ, êîìïëåìåíòàðíûå ðåòðîýëåìåíòàì ìëåêîïèòàþùèõ, ôîðìèðîâàòüñÿ çà ñ÷åò ïåðåêðûâàíèÿ ñìûñëîâîé è
àíòèñìûñëîâîé òðàíñêðèïöèè. Âåðîÿòíîñòü òàêîãî
ïåðåêðûâàíèÿ äîñòàòî÷íî âåëèêà, íî ïîêà äóïëåêñíûå
ÐÍÊ ðåòðîýëåìåíòîâ â ñîìàòè÷åñêèõ êëåòêàõ íå èäåíòèôèöèðîâàíû. Íå èäåíòèôèöèðîâàíû òàêæå äóïëåêñíûå ÐÍÊ,
ñ÷èòàííûå ñ òàíäåìíûõ ïîâòîðîâ «òåëîìåðíîãî» ãåòåðîõðîìàòèíà, èìåþùåãîñÿ ó íåêîòîðûõ âèäîâ ïîçâîíî÷íûõ,
êîòîðûé äèíàìè÷åñêè ñâÿçûâàåò áåëîê TRF1 è, ïî-âèäèìîìó, òðàíñêðèáèðóåòñÿ íà íèçêîì óðîâíå (Smirnova et al.,
2005; Svetlova et al., 2007) ïîäîáíî öåíòðîìåðíîìó ãåòåðîõðîìàòèíó.
Ýêñïåðèìåíòû ñ èñêóññòâåííîé ýêñïðåññèåé èíòåðôåðèðóþùèõ ÐÍÊ íå äàþò îñíîâàíèÿ ïðåäïîëàãàòü, ÷òî êàêèå-òî ïîñëåäîâàòåëüíîñòè íå ìîãóò ïðîöåññèðîâàòüñÿ
àïïàðàòîì ÐÍÊ-èíòåðôåðåíöèè. Ïî-âèäèìîìó, ëþáûå
ÐÍÊ-äóïëåêñû ìîãóò òðàíñôîðìèðîâàòüñÿ â siÐÍÊ è âûçûâàòü ïîäàâëåíèå ýêñïðåññèè êîìïëåìåíòàðíûõ ãåííûõ
ìèøåíåé ïóòåì èíòåðôåðåíöèè, à îáùèé êîíòðîëü îñóùåñòâëÿåòñÿ íà óðîâíå ðåãóëÿöèè àíòèñìûñëîâîé òðàíñêðèïöèè (ñì. ðèñóíîê).  ó÷àñòêàõ, ñîäåðæàùèõ àêòèâíûå
ãåíû, àíòèñìûñëîâàÿ òðàíñêðèïöèÿ, î÷åâèäíî, äîëæíà
áûòü ïîäàâëåíà, íàïðèìåð çà ñ÷åò ìóòàöèîííîé èíàêòèâàöèè ïîòåíöèàëüíûõ ïðîìîòîðîâ. Äðóãèì ýôôåêòèâíûì
ñïîñîáîì ïîäàâëåíèÿ àíòèñìûñëîâîé òðàíñêðèïöèè ÿâëÿåòñÿ òàêæå åå ðàííÿÿ òåðìèíàöèÿ, êîòîðàÿ ìîæåò îñóùåñòâëÿòüñÿ ïóòåì èíñåðöèè îïðåäåëåííûõ ðåòðîýëåìåíòîâ
â îäíîé îðèåíòàöèè. Ìîòèâ AATAAA (êîíñåíñóñíûé
ñàéò ïîëèàäåíèëèðîâàíèÿ ÐÍÊ) ðàáîòàåò êàê òåðìèíàòîð
òðàíñêðèïöèè, íî åãî àêòèâíîñòü ñèëüíî çàâèñèò îò îêðóæàþùèõ ïîñëåäîâàòåëüíîñòåé. Çàâèñèìàÿ îò îðèåíòàöèè
òåðìèíàöèÿ òðàíñêðèïöèè ÐÍÊ-ïîëèìåðàçîé II ïîñëåäîâàòåëüíîñòüþ, ñîäåðæàùåé CCAAT-áîêñ, èçâåñòíà óæå
äàâíî (Connelly, Manlet, 1989).
 çàêëþ÷åíèå ìîæíî îòìåòèòü, ÷òî ïîêà åùå ïðåæäåâðåìåííî ïðèíèìàòü ïðåäëîæåííóþ äëÿ öåíòðîìåðíîãî
ãåòåðîõðîìàòèíà S. pombe ìîäåëü (Kloc, Martienssen,
2008) êàê îáùóþ ìîäåëü ýïèãåíåòè÷åñêîãî íàñëåäîâàíèÿ.
Âî-ïåðâûõ, äëÿ ìëåêîïèòàþùèõ íå óñòàíîâëåíî, êàê ðåãóëèðóþòñÿ àíòèñìûñëîâàÿ òðàíñêðèïöèÿ, îáðàçîâàíèå
ìàëûõ ÐÍÊ è RITS-êîìïëåêñîâ â ñîìàòè÷åñêèõ êëåòêàõ.
Âî-âòîðûõ, íåêîòîðûå òèïû ãåòåðîõðîìàòèíà ïîääåðæèâàþòñÿ áåç ó÷àñòèÿ ìåòèëèðîâàíèÿ H3K9 è ìåòèëèðîâàíèÿ ÄÍÊ. Â-òðåòüèõ, èìåþòñÿ äàííûå î òîì, ÷òî íå òîëüêî ÐÍÊ-èíòåðôåðåíöèÿ èãðàåò ðîëü ïðè ýïèãåíåòè÷åñêèõ
ìîäèôèêàöèÿõ. Äàæå ó S. pombe èìåþòñÿ êàê çàâèñèìûå
òàê è íå çàâèñèìûå îò ÐÍÊ-èíòåðôåðåíöèè ïóòè îáðàçîâàíèÿ ãåòåðîõðîìàòèíà (Buhler et al., 2007). Ìåòèëèðîâàíèå ÄÍÊ íå çàâèñèò îò ÐÍÊ-èíòåðôåðåíöèè ó íåéðîñïîðû (Freitag et al., 2004), õîòÿ îíî è íàïðàâëÿåòñÿ ìåòèëèðîâàíèåì ãèñòîíîâ (Tamaru et al., 2003). Íå çàâèñèìûå îò
ÐÍÊ-èíòåðôåðåíöèè ïóòè ðåãóëÿöèè, îäíàêî ìîãóò âêëþ÷àòü â ñåáÿ äðóãèå ÐÍÊ-çàâèñèìûå ýëåìåíòû, íàïðèìåð
ÄÍÊ- è ÐÍÊ-ñâÿçûâàþùèå áåëêè. Âîçìîæíî, êîíå÷íî,
÷òî ñóùåñòâóþò è íåçàâèñèìûå îò òðàíñêðèïöèè ïóòè ðåãóëÿöèè ãåííîé ýêñïðåññèè, îäíàêî â íàñòîÿùåå âðåìÿ
íàèáîëåå àêòóàëüíûì ïðåäñòàâëÿåòñÿ èçó÷åíèå ãëîáàëüíîé ñàìîîðãàíèçàöèè ñìûñëîâîé è àíòèñìûñëîâîé òðàíñêðèïöèè â êëåòî÷íîì ÿäðå, ìåõàíèçìîâ åå èíèöèàöèè è
òåðìèíàöèè.
Ðàáîòà âûïîëíåíà ïðè ôèíàíñîâîé ïîääåðæêå ïðîãðàììû ïî ìîëåêóëÿðíîé è êëåòî÷íîé áèîëîãèè, à òàêæå
Ðîññèéñêîãî ôîíäà ôóíäàìåíòàëüíûõ èññëåäîâàíèé
(ïðîåêò 07-04-00311).
Ñïèñîê ëèòåðàòóðû
Alleman M., Sidorenko L., McGinnis K., Seshadri V., Dorweiler J. E., White J., Sikkink K., Chandler V. L. 2006. An RNA polymerase is required for paramutation in maize. Nature. 442 :
295—298.
Aravin A. A., Bourc’his D. 2008. Small RNA guides for d novo
DNA methylation in mammalian germ cells. Genes Develop. 22 :
970—975.
Aravin A. A., Hannon G. J., Brennecke J. 2007a. The Piwi-piRNA pathway provides an adaptive defense in the transposon
arms race. Science. 318 : 761—764.
Aravin A. A., Klenov M. S., Vagin V. V., Bantignie F., Cavalli G., Gvozdev V. A. 2004. Dissection of a natural RNA silencing
process in the Drosophila melanogaster germ line Mol. Cell. Biol.
24 : 6742—6750.
Íàñëåäîâàíèå ýïèãåíåòè÷åñêèõ ìîäèôèêàöèé õðîìàòèíà, íàïðàâëÿåìîå ÐÍÊ
Aravin A. A., Naumova N. M., Tulin A. V., Vagin V. V., Rozovsky Y. M., Gvozdev V. A. 2001. Double-stranded RNA-mediated silencing of genomic tandem repeats and transposable elements in the
D. melanogaster germline. Curr. Biol. 11 : 1017—1027.
Aravin A. A., Sachidanandam R., Girard A., Fejes-Toth K.,
Hannon G. J. 2007b. Developmentally regulated piRNA clusters
implicate MILI in transposon control. Science. 316 : 744—747.
Arita K., Ariyoshi M., Tochio H., Kawamura Y., Shirakawa M.
2008. Recognition of hemimethylated DNA by the SRA protein
UHRF1 by a base-flipping mechanism. Nature. 455 : 818—821.
Avvakumov G. V., Walker J. R., Xue S., Li Y., Duan S., Bronner C., Arrowsmith C. H., Dhe-Paganon S. 2008. Structural basis
for recognition of hemi-methylated DNA by the SRA domain of human UHRF1. Nature. 455 : 822—825.
Baulcombe D. 2004. RNA silencing in plants. Nature. 431 :
356—363.
Bernstein E., Denli A. M., Hannon G. J. 2001. The rest is silence. RNA. 7 : 1509—1521.
Bestor T. H. 2000. The DNA methyltransferases of mammals.
Hum. Mol. Genet. 9 : 2395—2402.
Bradbury E. M. 1992. Reversible histone modifications and the
chromosome cell cycle. Bioessays. 14 : 9—16.
Brink R. A. 1958. Paramutation at the R locus in maize. Cold
Spring Harbor Symp. Quant. Biol. 23 : 379—391.
Brockdorff N., Ashworth A., Kay G. F., Cooper P., Smith S.,
McCabe V. M., Norris D. P., Penny G. D., Patel D., Rastan S.
1991. Conservation of position and exclusive expression of mouse
Xist from the inactive X chromosome. Nature. 351 : 329—331.
Brockdorff N., Ashworth A., Kay G. F., McCabe V. M., Norris D. P., Cooper P. J., Swift S., Rastan S. 1992. The product of
the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell. 71 : 515—
526.
Buhler M., Haas W., Gygi S. P., Moazed D. 2007. RNAi-dependent and -independent RNA turnover. Cell. 129 : 707—721.
Cam H. P., Sugiyama T., Chen E. S., Chen X., FitzGerald P. C., Grewal S. I. 2005. Comprehensive analysis of heterochromatin- and RNAi-mediated epigenetic control of the fission yeast
genome. Nat. Genet. 37 : 809—819.
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M. C.,
Maeda N. et al. 2005. The transcriptional landscape of the mammalian genome. Science. 309 : 1559—1563.
Chen E. S., Zhang K., Nicolas E., Cam H. P., Zofall M., Grewal S. I. 2008. Cell cycle control of centromeric repeat transcription and heterochromatin assembly. Nature. 451 : 734—737.
Chung W. J., Okamura K., Martin R., Lai E. C. 2008. Endogenous RNA interference provides a somatic defense against Drosophila transposons. Curr. Biol. 18 : 795—802.
Connelly S., Manley J. L. 1989. RNA polymerase II transcription termination is mediated specifically by protein binding to a
CCAAT box sequence. Mol. Cell. Biol. 9 : 5254—5259.
Cuzin F., Grandjean V., Rassoulzadegan M. 2008. Inherited
variation at the epigenetic level: paramutation from the plant to the
mouse. Curr. Opin. Genet. Develop. 18 : 93—196.
Dong K. B., Maksakova I. A., Mohn F., Leung D., Appanah R.,
Lee S., Yang H. W., Lam L. L., Mager D. L., Schübeler D., Tachibana M., Shinkai Y., Lorincz M. C. 2008. DNA methylation in ES
cells requires the lysine methyltransferase G9a but not its catalytic
activity. EMBO J. Sep. 25.
Fire A., Xu S., Montgomery M. K., Kostas S. A., Driver S. E.,
Mello C. C. 1998. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 391 : 806—
811.
Fischle W., Tseng B. S., Dormann H. L., Ueberheide B. M.,
Garcia B. A., Shabanowitz J., Hunt D. F., Funabiki H., Allis C. D.
2005. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature. 438 : 1116—1122.
Freitag M., Lee D. W., Kothe G. O., Pratt R. J., Aramayo R.,
Selker E. U. 2004. DNA methylation is independent of RNA interference in Neurospora. Science. 304 : 1939.
Goodier J. L., Kazazian H. 2008. Retrotransposons revisited:
the restraint and rehabilitation of parasites. Cell. 135 : 23—35.
295
Groth A., Corpet A., Cook A. J., Roche D., Bartek J., Lukas J.,
Almouzni G. 2007. Regulation of replication fork progression
through histone supply and dem and. Science. 318 : 1928—
1931.
Gullerova M., Proudfoot N. J. 2008. Cohesin complex promotes transcriptional termination between convergent genes in S. pombe. Cell. 132 : 983—995.
Hannon G. J. 2002. RNA interference. Nature. 418 : 244—251.
Hashimoto H., Horton J. R., Zhang X., Bostick M., Jacobsen S. E., Cheng X. 2008. The SPA domain of UNRF1 flips 5-methylcytosine out of the DNA helix. Nature. 455 : 826—829.
Heard E. 2005. Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome. Curr.
Opin. Genet. Develop. 15 : 482—489.
Hirota T., Lipp J. J., Toh B. H., Peters J. M. 2005. Histone H3
serine 10 phosphorylation by Aurora B causes HP1 dissociation
from heterochromatin. Nature. 438 : 1176—1180.
Iida T., Nakayama J., Moazed D. 2008. siRNA-mediated heterochromatin establishment requires HP1 and is associated with antisense transcription. Mol. Cell. 31 : 178—189.
Jackson J. P., Lindroth A. M., Cao X., Jacobsen S. E. 2002.
Control of CpNpG DNA methylation by the KRYPTONITE histone
H3 methyltransferase. Nature. 416 : 556—560.
Jenuwein T., Allis C. D. 2001. Translating the histone code.
Science. 293 : 1074—1080.
Kapranov P., Willingham A. T., Gingeras T. R. 2007. Genome-wide transcription and the implications for genomic organization. Nat. Rev. Genet. 8 : 413—423.
Kawamura Y., Saito K., Kin T., Ono Y., Asai K., Sunohara T.,
Okada T. N., Siomi M. C., Siomi H. 2008. Drosophila endogenous
small RNAs bind to Argonaute 2 in somatic cells. Nature. 453 :
793—797.
Kloc A., Martienssen R. 2008. RNAi, heterochromatin and the
cell cycle. Trends Genet. Sep. 6.
Klos A., Zaratiegui M., Nora E., Martienssen R. 2008. RNA
interference guides histone modification during the S phase of chromosomal replication. Curr. Biol. 18 : 490—495.
Kuramochi-Miyagawa S., Watanabe T., Gotoh K., Totoki Y.,
Toyoda A., Ikawa M., Asada N., Kojima K., Yamaguchi Y., Ijiri T. W., Hata K., Li E., Matsuda Y., Kimura T., Okabe M., Sakaki Y., Sasaki H., Nakano T. 2008. DNA methylation of retrotransposon genes is regulated by Piwi family members MILI and MIWI2 in
murine fetal testes. Genes. Develop. 22 : 908—917.
Lee R. C., Feinbaum R. L., Ambros V. 1993. The C. elegans
heterocxhronic gene lin-4 encodes small RNAs with antisense complementary to lin-14. Cell. 75 : 843—854.
Lehnertz B., Ueda Y., Derijck A. A., Braunschweig U., Perez-Burgos L., Kubicek S., Chen T., Li E., Jenuwein T., Peters A. H.
2003. Suv39h-mediated histone He lysine 9 methylation directs
DNA methylation of major satellite repeats at pericentric heterochromatin. Curr. Biol. 13 : 1192—1200.
Levanon K., Eisenberg E., Rechavi G., Levanon E. Y. 2005.
Letter from the editor: Adenosine-toinosine RNA editing in Alu repeats in the human genome. EMBO Rep. 6 : 831—835.
Ley-Maor G., Ram O., Kim E., Sela N., Goren A., Levanon E. Y., Ast G. 2008. Intronic Alus influence alternative splicing.
PLoS Genet. 4 paper e1000204.
Lippman Z., Martienssen R. 2004. The role of RNA interference in heterochromatic silencing. Nature. 431 : 364—370.
Lu J., Gilbert D. M. 2008. Cell cycle regulated transcription of
heterochromatin in mammals vs. fission yeast: functional conservation or coincidence? Cell Cycle. 7 : 1907—1910.
Martienssen R. A., Zaratiegui M., Goto D. B. 2005. RNA interference and heterochromatin in the fission yeast Schizosaccharomyces pombe. Trends Genet. 21 : 450—456.
Mattick J. S. 2007. A new paradigm for developmental biology. J. Exp. Biol. 210 : 1526—1547.
Matzke M. A., Matzke A. J. 2004. Planting the seeds of a new
paradigm. PLoS Biol. 2 paper E133.
Nishikura K. 2006. Editor meets silencer: crosstalk between
RNA editing and RNA interference. Nat. Rev. Mol. Cell. Biol. 7 :
919—931.
296
Í. Â. Òîìèëèí
Obbard D. J., Finnegan D. J. 2008. RNA interference: endogenous siRNAs derived from transposable elements. Curr. Biol.
18 : R561—R563.
Ogawa Y., Sun B. K., Lee J. T. 2008. Intersection of the RNA
interference and X-inactivation pathways. Science. 320 :
1336—1341.
Okamura K., Balla S., Martin R., Liu N., Lai E. C. 2008. Two
distinct mechanisms generate endogenous siRNAs from bidirectional transcription in Drosophila melanogaster. Nat. Struct. Mol.
Biol. 15 : 581—590.
Rassoulzadegan M., Grandjean V., Gounon P., Vincent S., Gillot I., Cuzin F. 2006. RNA-mediated non-mendelian inheritance of
an epigenetic change in the mouse. Nature. 441 : 469—474.
Ryazansky S. S., Gvozdev V. A. 2007. Small RNAs and cancerogenesis. Biochemistry (Mosc.). 73 : 514—527.
Sakamoto Y., Watanabe S., Ichimura T., Kawasuji M., Koseki H., Baba H., Nakao M. 2007. Overlapping roles of the methylated DNA-binding protein MBD1 and polycomb groups proteins in
transcriptional repression of HOXA genes and heterochromatin foci
formation. J. Biol. Chem. 282 : 16 391—16 400.
Sarraf S. A., Stancheva I. 2004. Methyl-CpG binding protein
MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to
DNA replication and chromatin assembly. Mol. Cell. 15 : 595—
605.
Smirnova A. N., Krutilina R. I., Tomilin N. V. 2005. Dynamic
binding of the telomeric human protein TRF1 to intrachromosomal
blocks (TTAGGG)n in living Chinese hamster cells depends on
transcription. Mol. Biol. (Mosc.). 39 : 978—983.
Strahl B. D., Allis C. D. 2000. The language of covalent histone modifications. Nature. 403 : 41—45.
Strunnikova M., Schagdarsurengin U., Kehlen A., Garbe J. C.,
Stampfer M. R., Dammann R. 2005. Chromatin inactivation precedes de novo DNA methylation during the progressive epigenetic si-
lencing of the RASSF1A promoter. Mol. Cell. Biol. 25 : 3923—
3933.
Svetlova M. P., Solovjeva L. V., Smirnova A. N., Tomilin N. V.
2007. Long interstitial (TTAGGG)n arrays do not colocalize with
repressive chromatin modification in Chinese hamster cells. Cell
Biol. Int. 31 : 308—315.
Tachibana M., Matsumura Y., Fukuda M., Kimura H., Shinkai Y. 2008. G9a/GLP complexes independently mediate H3K9
and DNA methylation ot silence transcription. EMBO J.
Sep. 25.
Tamaru H., Zhang X., McMillen D., Singh P. B., Nakayama J.,
Grewal S. I., Allis C. D., Cheng X., Selker E. U. 2003. Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa. Nat. Genet. 34 : 75—79.
Thon G. 2008. Histone modifications: cycling with chromosomal replication. Curr. Biol. 18 : R380—R382.
Tomilin N. V. 2008. Regulation of mammalian gene expression
by retroelements and non-coding tandem repeats. Bioessays. 303 :
338—348.
Vaniushin B. F. 2006. DNA methylation and epigenetics. Genetika (Mosc.). 42 : 1186—1199.
Volpe T. A., Kidner C., Hall I. M., Teng G., Grewal S. I., Martienssen R. A. 2002. Regulation of heterochromatic silencing and
histone H3 lysine-9 methylation by RNAi. Science. 297 :
1833—1837.
Wassenegger M., Neimes S., Riedel L., Sanger H. L. 1994.
RNA-directed de novo methylation of genomic sequences in plants.
Cell. 76 : 567—576.
Yoder J. A., Soman N. S., Verdine G. L., Bestor T. H. 1997.
DNA (cytosine-5)-methyltransferases in mouse cells and tissues.
Studies with a mechanism-based probe. J. Mol. Biol. 270 :
385—395.
Ïîñòóïèëà 5 XI 2008
INHERITANCE OF RNA-DIRECTED EPIGENETIC MODIFICATIONS OF CHROMATIN
N. V. Tomilin
Institute of Cytology RAS, St. Petersburg; e-mail: nvtom@mail.ru
Published data are reviewed on the mechanism of inheritance of repressive epigenetic modifications of
chromatin, histone and DNA, which suggest that they depend on RNA. RNA is transcribed from most of genome compartments and when it forms duplex structures because of overlapping transcription or because of resynthesis by RNA-dependent RNA polymerase, heterochromatin is generated. Mitotic phosphorylation of Ser-10 in
histone H3 stimulates transcription of heterochromatin and its recovery in the next cell cycle by RNA interference.
K e y w o r d s: epigenetics, modifications of histones, chromatin, methylation of DNA.