Tài liệu Báo cáo khoa học: Gene silencing at the nuclear periphery pdf

MINIREVIEW

Gene silencing at the nuclear periphery

Sigal Shaklai, Ninette Amariglio, Gideon Rechavi and Amos J. Simon

Sheba Cancer Research Center and the Institute of Hematology, The Chaim Sheba Medical Center, Tel Hashomer and the Sackler School of

Medicine, Tel Aviv University, Israel

The nuclear lamina

The nuclear envelope (NE), which separates the nucleus

from the cytoplasm, consists of the outer (ONM) and

inner (INM) nuclear membranes and nuclear pore com￾plexes (NPCs). The ONM is continuous with the endo￾plasmic reticulum (ER). The INM and ONM are

separated by a lumenal space, but join at sites that

are occupied by NPCs, which mediate bidirectional

transport of macromolecules between the cytoplasm

and the nucleus. The luminal space between the ONM

and INM is crossed by giant protein complexes

that bridge the NE and mechanically couple the cyto￾skeleton to the nucleoskeleton (reviewed in [1]). In

Keywords

epigenetics; gene silencing;

heterochromatin; histone modifications;

LAP2; laminopathies; nuclear envelope;

nuclear envelopathies; nuclear lamina;

transcription

Correspondence

A. J. Simon, Sheba Cancer Research Center

and the Institute of Hematology, The Chaim

Sheba Medical Center, Tel Hashomer and

the Sackler School of Medicine, Tel Aviv

University, Israel

Fax: 972 3 530 5351

Tel: 972 3 530 5814

E-mail: [email protected]

(Received 21 August 2006, revised 4

January 2007, accepted 8 January 2007)

doi:10.1111/j.1742-4658.2007.05697.x

The nuclear envelope (NE) is composed of inner and outer nuclear mem￾branes (INM and ONM, respectively), nuclear pore complexes and an

underlying mesh like supportive structure – the lamina. It has long been

known that heterochromatin clusters at the nuclear periphery adjacent to

the nuclear lamina, hinting that proteins of the lamina may participate in

regulation of gene expression. Recent studies on the molecular mechanisms

involved show that proteins of the nuclear envelope participate in regula￾tion of transcription on several levels, from direct binding to transcription

factors to induction of epigenetic histone modifications. Three INM pro￾teins; lamin B receptor, lamina-associated polypeptide 2b and emerin, were

shown to bind chromatin modifiers and ⁄ or transcriptional repressors indu￾cing, at least in one case, histone deacetylation. Emerin and another INM

protein, MAN1, have been linked to down-regulation of specific signaling

pathways, the retino blastoma 1 ⁄E2F MyoD and transforming growth fac￾tor beta ⁄ bone morphogenic protein, respectively. Therefore, cumulative

data suggests that proteins of the nuclear lamina regulate transcription by

recruiting chromatin modifiers and transcription factors to the nuclear per￾iphery. In this minireview we describe the recent literature concerning

mechanisms of gene repression by proteins of the NE and suggest the

hypothesis that the epigenetic ‘histone code’, dictating transcriptional

repression, is ‘written’ in part, at the NE by its proteins. Finally, as aber￾rant gene expression is one of the mechanisms speculated to underlie the

newly discovered group of genetic diseases termed nuclear envelo￾pathies⁄ laminopathies, elucidating the repressive role of NE proteins is a

major challenge to both researchers and clinicians.

Abbreviations

BAF, barrier-to-autointegration factor; EDMD, Emery–Dreifuss muscular dystrophy; GCL, germ cell less; HDAC, histone deacetylase;

HP1, heterochromatin protein 1; IBSN, infantile bilateral striatal necrosis; INM, inner nuclear membrane; KASH, Klarsicht, ANC-1 and SYNE1

homology; LAP2b, lamina-associated polypeptide 2b; LBR, lamin B receptor; LEM domain, LAP2-emerin-MAN1 domain; ONM, outer nuclear

membrane; NE, nuclear envelope; NES1, Nesprin-1; NES2g, Nesprin-2 giant; NPC, nuclear pore complexes; pRb, retinoblastoma protein;

SREBP, sterol response element binding protein; SUN, S-phase arrest defective 1 and UNC-84 homology.; TGFb/BMP, transforming growth

factor beta ⁄ bone morphogenic protein.

FEBS Journal 274 (2007) 1383–1392 ª 2007 The Authors Journal compilation ª 2007 FEBS 1383