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

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
particular, SUN (S-phase arrest defective 1 and UNC-
84 homology) domain family of nuclear envelope pro-
teins, such as Caenorhabditis elegans UNC-84 [2] and
matefin ⁄ SUN-1 [3], interacts with various KASH
[Klarsicht, actin-noncomplementing (ANC-1) and synap-
tic nuclear envelope-1 (SYNE1) homology] domain
partners, such as ANC-1 [4], UNC-83 [5], and ZYG-12
[6], to form SUN domain-dependent ‘bridges’ across the
inner and outer nuclear membranes. In this network of
SUN–KASH interactions UNC-84 can bind either
ANC-1, which binds actin, or UNC-83, which binds
microtubules via an unidentified microtubule-dependent
motor protein. Matefin ⁄ SUN-1 binds ZYG-12 dimers,
which bind the microtubule-organizing centre. Human
proteins SUN1 and SUN2 anchor Nesprin-2 (also
known as syne-2 and NUANCE) giant (NES2g) at the
ONM. NES2g and Nesprin-1 (also known as CPG2,
syne-1, myne-1 and Enaptin) giant isoform (NES1g),
each bind actin. Nesprin-3 (NES3) binds plectin, which
links cytoplasmic intermediate filaments to actin
(reviewed in [1,7,8]). These bridges physically connect
the nucleus to component of the cytoskeleton. By ser-

development. During mitosis the B-type lamins are
found in a membrane-bound form, attached to the dis-
assembled inner nuclear membranes (and their associ-
ating proteins), suggesting their complete cellular
segregation from A-type lamins when the NE is disas-
sembled [10a]. In mammalian cells lamins bind in vitro
to many known INM proteins, including emerin,
MAN1, lamin B receptor (LBR), lamina-associated
polypeptides-1 and 2 (LAP1, LAP2) isoforms and Nes-
prin-1a. In addition, lamins bind nucleoplasmic soluble
proteins, such as the chromatin histones H2A and H2B
dimers and barrier-to-autointegration factor (BAF), as
well as LAP2a, Kruppel-like protein (MOK2), actin,
retinoblastoma protein (RB), sterol response element
binding protein (SREBP), components of RNA polym-
erase II-dependent transcription complexes and DNA
replication complexes [22,23]. Mutations in lamins and
lamin-binding proteins cause a wide range of heritable
or sporadic human diseases, which are collectively
known as the ‘nuclear envelopathies’ or ‘laminopathies’
[24–26]. The majority of these disorders were linked to
mutations in A-type lamins. However, mutations in four
integral INM lamin binding proteins have also been
implicated as a cause of ‘nuclear envelopathies’. Of the
four proteins LBR, emerin, LAP2 and MAN1, the three
latter share the conserved 40 amino acid chromatin
binding LAP2-emerin-MAN1 (LEM) domain [27,28].
Heterochromatin and the nuclear
periphery
Various studies have established that a correlation

domains. A clue to the mechanism by which intranu-
clear translocation occurs comes from the work of Chu-
ang and colleagues; they showed that migration of an
interphase chromosome locus from the nuclear periph-
ery to the nuclear center upon activation is disrupted
by specific actin or nuclear myosin mutants [45]. While
INM proteins in metazoans have been shown to func-
tion as repressors of transcription, gene regulation at
the nuclear periphery is probably a much more complex
process. Recent studies in yeast suggest that proteins of
the nuclear pore complex the nucleoporins (NUPS)
function as inhibitors of gene repression or rather as
activators of transcription. The nucleoporin Nup2p was
shown to tether chromatin to the nuclear pore complex
(NPC) blocking propagation of heterochromatin. Fur-
thermore, interaction of Nup2p with numerous genes
leads to their activation in what was coined the nucleo-
pore to-gene-promoter interaction (Nup-PI) [46]. Simi-
larly, transcriptionaly activated GAL1 genes are
preferentially found at the nuclear periphery where they
are linked to the NPC component Nup1 by SAGA
interacting factors [47]. These studies support the
notion that positioning of genes in the nuclear space
correlates to their transcriptional activity, still leaving
many unanswered questions as to the molecular mecha-
nisms by which repositioning is transacted.
Transcriptional repression by proteins
of the nuclear envelope
Peripherally located, transcriptionally silent chromatin
has distinctive structural characteristics (at the DNA

in B receptor (LBR) was found to associate with
heterochromatin protein 1 (HP1) and histones H3 ⁄ H4
under deacetylating conditions [50]; 2. lamina-associ-
ated polypeptide 2b (LAP2b) was shown by us to bind
the transcriptional repressors germ cell less (GCL) [19]
and histone deacetylase 3 (HDAC3) resulting in the
latter case in deacetylation of histone H4 [20]; 3. Emerin
was shown to associate with the death promoting fac-
tor Btf [51], the splicing associated factor YT521-B
[52] and similar to LAP2b, with the transcriptional
repressor GCL [53]. Other components of the nuclear
lamina shown to interact with transcriptional regula-
tors include LAP2a, a nucleoplasmic LAP2 isoform,
and lamin A ⁄ C [54–56]. LAP2a was shown to complex
with lamin A ⁄ C and the retinoblastoma protein (pRb).
Reduced levels of LAP2a or its aberrant localization
caused mislocalization of pRb suggesting that LAP2a
and lamin A ⁄ C serve as anchoring sites for this protein
[55]. As mentioned, lamin A ⁄ C interacts with histones,
components of the RNA II polymerase transcriptional
complex (reviewed in [10]), SREBP [57] and dephos-
phorylated pRb [55]. With regard to transcription, two
INM LEM domain proteins, MAN1 and emerin, have
been linked to specific pathways. MAN1 has been
shown to antagonize TGFb ⁄ BMP signaling through
binding to receptor-regulated Smads [sma (C. elegans)
and mothers against decapentaplegic (DPP, Droso-
phila) homologues], inhibiting downstream signaling
and preventing normal ventralization in Xenopus laevis
embryos [58–60,60a]. Emerin loss, responsible for

modifications. Its complexity results from the enor-
mous number of combinations of modification type,
number and sites on which they occur in each histone.
For example, histone H3 can be acetylated on its
lysine 9 (later on written as H3 K9 acetylation), phos-
phorylated on the adjacent serine 10 residue and
methylated on its lysine 27, individually or all at the
same time. Further complexity results from the possi-
bility of single lysine and arginine residues to undergo
mono-, di- or tri- (in the case of lysine) methylation.
The histone code influences the structure of the chro-
matin fiber aiding or abating its ability to undergo
transcription at that point. Site-specific combinations
of histone modifications have been shown to correlate
with transcriptional activation or repression. For
example, the combination of H4 K8 acetylation, H3
K14 acetylation, and H3 S10 phosphorylation is often
associated with transcriptional activation. Conversely,
tri-methylation of H3 K9 and the lack of H3 and H4
acetylation correlate with transcriptional repression
(reviewed in [64,65]). Evidence points to the concentra-
tion of transcriptionally inactive heterochromatin,
lacking histone acetylation at the nuclear periphery as
opposed to acetylated, transcriptionaly competent euchro-
matin at the nuclear interior [66].
Nuclear envelopathies ⁄ laminopathies
and gene repression
Mutations in proteins of the nuclear lamina have been
shown to cause a wide array of genetic diseases termed
nuclear envelopathies ⁄ laminopathies [24–26]. Although

mutated nup62 causes autosomal recessive familial
infantile bilateral striatal necrosis (IBSN) severe neuro-
logical disorder [72], IBSN is characterized by symmet-
rical degeneration of the caudate nucleus, putamen,
and occasionally the globus pallidus, with little involve-
ment of the rest of the brain.
The question of how mutations in the same gene or
group of genes, which are ubiquitously expressed, cause
such a wide variety of tissue specific diseases has linked
the laminopathies to the study of transcription regula-
tion. Two major models attempt to explain how
mutated lamins and NE proteins lead to the observed
pathologies: the mechanical stress model and the gene
expression model. The mechanical stress model suggests
that nuclei that contain defective lamin or emerin pro-
teins might be mechanically more fragile than their
wildtype counterparts. This model relies on studies in
C. elegans, D. melanogaster and mice, showing dra-
matic defects in NE structure in nuclei that are deficient
in lamins, and that this fragility could ultimately lead
to nuclear damage and cell death [68]. The idea of
enhanced nuclear fragility is particularly attractive as
an explanation for the cardiac- and skeletal-muscle
pathologies, as the forces that are generated during
Gene silencing at the nuclear periphery S. Shaklai et al.
1386 FEBS Journal 274 (2007) 1383–1392 ª 2007 The Authors Journal compilation ª 2007 FEBS
muscle contraction might potentially lead to preferen-
tial breakage of nuclei that contain a defective nuclear
lamina. Nuclei in noncontractile tissues might remain
relatively unscathed, despite showing abnormal nuclear

of heterochromatin at the nuclear periphery [76]. Simi-
larly, light and electron microscopy analyses of HGPS
fibroblasts reveal significant changes in nuclear shape,
including lobulation of the nuclear envelope, thickening
of the nuclear lamina, loss of peripheral heterochroma-
tin, and clustering of nuclear pores [77]. These struc-
tural defects worsen as HGPS cells age in culture. The
authors suggest that nuclear lamina defects in these
cells are due to the disruption of lamin-related func-
tions, ranging from the maintenance of nuclear shape
to regulation of gene expression and DNA replication.
Goldman and colleagues further analyzed the mecha-
nisms responsible for the loss of heterochromatin in
cells of HPGS patients [78]. For this purpose epigenetic
marks regulating facultative and constitutive hetero-
chromatin were examined. In cells originating from a
female HGPS patient, the transcriptionally repressive
histone H3 trimethylated on lysine 27 (H3 K27me3)
marker of facultative heterochromatin, was lost on the
inactive X chromosome (Xi). The methyltransferase
responsible for this epigenetic modification, EZH2, was
down-regulated. These alterations were detectable
before the changes in nuclear shape, reported earlier
[77]. Another transcriptionally repressive epigenetic
mark, histone H3 trimethylated on lysine 9 (H3
K9me3) which marks pericentric constitutive hetero-
chromatin, was down-regulated in these cells. This
change correlated with an altered association of the
H3K9me3 with HP1a and the calcinosis, Raynauds
phenomenon, esophageal dysmotility, sclerodactyly, tel-

nuclei the peripheral localization of condensed hetero-
chromatic regions and the more centered localization
of diffused euchromatic regions. RNA synthesis was
more active in the diffused interior euchromatin than
in the condensed peripheral heterochromatin [81]. The
heterochromatic sex-chromatin body of Barr, which in
female mammalian cells is composed of a segment of
one X chromosome, was found by this group to carry
unexpressed genes. The DNA of this inactivated
X chromosome replicated later than that of other
S. Shaklai et al. Gene silencing at the nuclear periphery
FEBS Journal 274 (2007) 1383–1392 ª 2007 The Authors Journal compilation ª 2007 FEBS 1387
chromosomal segments [82]. Today we know that
the inactivated X chromosome resides at the nuclear
periphery and we use it as a compelling example of
chromosome-wide, long-range epigenetic gene silencing
in mammals (reviewed in [83]). Since the fundamental
discoveries by the group of Mirsky the development of
experimental tools, such as fluorescence in situ hybrid-
ization combined with three-dimensional microscopy,
to analyze chromosomes and proteins in living cells,
together with complementary approaches that explore
the computational biology, epigenetic modifications
and gene expression profiling along the chromosomes,
offer us today the possibility of visualizing ‘real time’
gene expression. We can follow the looping out or
‘jumping’ of loci from their gene repressed heterochro-
matic territory at the nuclear periphery to more inter-
nal gene active euchromatic territories for their
transcription [34,45,84,85]. However, still little is

matin, such that specific loci and genes are transcrip-
tionally inhibited. Our model, based on LAP2b and
Fig. 1. Gene silencing at the nuclear periphery. The ONM is a continuation of the endoplasmic reticulum. It joins the INM at the NPCs.
Lamins A ⁄ C (black line) and B (red line) are shown as filaments at the nuclear periphery and across the nucleoplasm (lamin A ⁄ C). Associa-
tions of the INM proteins LAP2b, LBR, emerin and MAN1 with lamins, chromatin and their specific partners are shown: LAP2b binds
BAF, HDAC3, GCL and HA95; LBR binds HP1, histones H3 and H4; MAN1 binds BAF and GCL, emerin binds BAF and GCL competitively,
YT521-B and actin. The question marks indicate, yet unidentified, LAP2b-associating proteins catalyzing gene silencing through epigenetic
modifications. The two chromatin states, of gene-active unwrapped euchromatin at the nucleoplasm, and of gene-silenced condensed
heterochromatin at the vicinity of the INM are circled. In the latter state, epigenetic modifications on histones and DNA are illustrated. The
intranuclear complex containing LAP2a, lamin A, Rb and BAF proteins is shown. C, cytosol; NL, nuclear lamina; NP, nucleoplasm; NPC, nuc-
lear pore complex; ONM, outer nuclear membrane; INM, inner nuclear membrane; H-Chr (GR), heterochromatin (gene repression); Ec-Chr
(GA), euchromatin (gene activation); Me, methylation; deAC, deacetylation; Ri, ribosylation; Ub, ubiquitination; P, phosphorylation.
Gene silencing at the nuclear periphery S. Shaklai et al.
1388 FEBS Journal 274 (2007) 1383–1392 ª 2007 The Authors Journal compilation ª 2007 FEBS
LBR studies, suggests that two collaborative under-
acetylated chromatin complexes are formed at and
anchored to the NE. In one complex, LAP2b recruits
the enzyme (HDAC3) while in the other complex LBR
recruits the substrates (histones H3 ⁄ H4) [20,50]. In
both cases, acetylation conditions, alleviated the
LAP2b ⁄ HDAC3 dependent transcriptional repression
[20] or dissociated the LBR–HP1–histones repressive
complex [50].
The proposed concept places proteins of the nuclear
lamina as high hierarchical transcriptional regulators.
This may have implications in the study of cancer dis-
eases, where a strong link was established in recent
years between gene inactivation and tumorigenesis,
mainly in hematological malignancies [63], and
NE ⁄ lamina associated diseases and ageing in which

JM, Ahringer J & White JG (2003) The C. elegans hook
protein, ZYG-12, mediates the essential attachment
between the centrosome and nucleus. Cell 115, 825–836.
7 Warren DT, Zhang Q, Weissberg PL & Shanahan CM
(2005) Nesprins: intracellular scaffolds that maintain cell
architecture and coordinate cell function? Expert Rev
Mol Med 7, 1–15.
8 Starr DA & Fischer JA (2005) KASH ‘’n Karry: the
KASH domain family of cargo-specific cytoskeletal
adaptor proteins. Bioessays 27, 1136–1146.
9 Haque F, Lloyd DJ, Smallwood DT, Dent CL, Shana-
han CM, Fry AM, Trembath RC & Shackleton S
(2006) SUN1 interacts with nuclear lamin A and cyto-
plasmic nesprins to provide a physical connection
between the nuclear lamina and the cytoskeleton. Mol
Cell Biol 26, 3738–3751.
10 Gruenbaum Y, Margalit A, Goldman RD, Shumaker
DK & Wilson KL (2005) The nuclear lamina comes of
age. Nat Rev Mol Cell Biol 6, 21–31.
10a Bridger JM, Foeger N, Kill IR & Herrmann H (2007)
The nuclear lamina. Both a structural framework and a
platform for genome organization. FEBS J 274,
doi:10.1111 ⁄ j.1742–4658.2007.05694.x
11 Liu J, Ben-Shahar TR, Riemer D, Treinin M, Spann P,
Weber K, Fire A & Gruenbaum Y (2000) Essential roles
for Caenorhabditis elegans lamin gene in nuclear organi-
zation, cell cycle progression, and spatial organization
of nuclear pore complexes. Mol Biol Cell 11, 3937–3947.
12 Liu J, Lee KK, Segura-Totten M, Neufeld E, Wilson
KL & Gruenbaum Y (2003) MAN1 and emerin have

NG, Gilbert DJ, Jenkins NA, Berger R, Shaklai S,
Amariglio N et al. (2001) Nuclear membrane protein
LAP2beta mediates transcriptional repression alone and
together with its binding partner. GCL (Germ-Cell-
Less) J Cell Sci 114, 3297–3307.
20 Somech R, Shaklai S, Geller O, Amariglio N, Simon
AJ, Rechavi G & Gal-Yam EN (2005) The nuclear-
envelope protein and transcriptional repressor LAP2-
beta interacts with HDAC3 at the nuclear periphery,
and induces histone H4 deacetylation. J Cell Sci 118,
4017–4025.
21 Schirmer EC, Florens L, Guan T, Yates JR III &
Gerace L (2003) Nuclear membrane proteins with
potential disease links found by subtractive proteomics.
Science 301, 1380–1382.
22 Gruenbaum Y, Goldman RD, Meyuhas R, Mills E,
Margalit A, Fridkin A, Dayani Y, Prokocimer M &
Enosh A (2003) The nuclear lamina and its functions in
the nucleus. Int Rev Cytol 226, 1–62.
23 Zastrow MS, Vlcek S & Wilson KL (2004) Proteins that
bind A-type lamins: integrating isolated clues. J Cell Sci
117, 979–987.
24 Somech R, Shaklai S, Amariglio N, Rechavi G &
Simon AJ (2005) Nuclear envelopathies – raising the
nuclear veil. Pediatr Res 57, 8R–15R.
25 Burke B & Stewart CL (2006) The laminopathies: the
functional architecture of the nucleus and its contribu-
tion to disease. Annu Rev Genomics Hum Genet 7, 369–
405.
26 Mattout A, Dechat T, Adam SA, Goldman RD &

Centromeric Heterochromatin. Cell 91, 845–854.
34 Kosak ST, Skok JA, Medina KL, Riblet R, Le Beau
MM, Fisher AG & Singh H (2002) Subnuclear compart-
mentalization of immunoglobulin loci during lympho-
cyte development. Science 296, 158–162.
35 Gerasimova TI, Byrd K & Corces VG (2000) A chro-
matin insulator determines the nuclear localization of
DNA. Mol Cell 6, 1025–1035.
36 Francastel C, Magis W & Groudine M (2001) Nuclear
relocation of a transactivator subunit precedes target
gene activation. Proc Natl Acad Sci USA 98, 12120–
12125.
37 Imai S, Nishibayashi S, Takao K, Tomifuji M, Fujino
T, Hasegawa M & Takano T (1997) Dissociation of
Oct-1 from the nuclear peripheral structure induces the
cellular aging-associated collagenase gene expression.
Mol Biol Cell 8, 2407–2419.
38 Robinett CC, Straight A, Li G, Willhelm C, Sudlow G,
Murray A & Belmont AS (1996) In vivo localization of
DNA sequences and visualization of large-scale chroma-
tin organization using lac operator ⁄ repressor recogni-
tion. J Cell Biol 135, 1685–1700.
39 Tumbar T, Sudlow G & Belmont AS (1999) Large-scale
chromatin unfolding and remodeling induced by VP16
acidic activation domain. J Cell Biol 145 , 1341–1354.
40 Ye Q, Hu YF, Zhong H, Nye AC, Belmont AS & Li R
(2001) BRCA1-induced large-scale chromatin unfolding
and allele-specific effects of cancer-predisposing muta-
tions. J Cell Biol 155, 911–921.
41 Nye AC, Rajendran RR, Stenoien DL, Mancini MA,

the Drosophila melanogaster genome at the nuclear
lamina. Nat Genet 38, 1005–1014.
49 Makatsori D, Kourmouli N, Polioudaki H, Shultz LD,
McLean K, Theodoropoulos PA, Singh PB & Georga-
tos SD (2004) The inner nuclear membrane protein
lamin B receptor forms distinct microdomains and links
epigenetically marked chromatin to the nuclear envel-
ope. J Biol Chem 279, 25567–25573.
50 Polioudaki H, Kourmouli N, Drosou V, Bakou A,
Theodoropoulos PA, Singh PB, Giannakouros T &
Georgatos SD (2001) Histones H3 ⁄ H4 form a tight
complex with the inner nuclear membrane protein LBR
and heterochromatin protein 1. EMBO Rep 2, 920–925.
51 Haraguchi T, Holaska JM, Yamane M, Koujin T,
Hashiguchi N, Mori C, Wilson KL & Hiraoka Y (2004)
Emerin binding to Btf, a death-promoting transcrip-
tional repressor, is disrupted by a missense mutation
that causes Emery-Dreifuss muscular dystrophy. Eur J
Biochem 271, 1035–1045.
52 Wilkinson FL, Holaska JM, Zhang Z, Sharma A,
Manilal S, Holt I, Stamm S, Wilson KL & Morris GE
(2003) Emerin interacts in vitro with the splicing-asso-
ciated factor Yt521-B. Eur J Biochem 270, 2459–2466.
53 Holaska JM, Lee KK, Kowalski AK & Wilson KL
(2003) Transcriptional repressor germ cell-less (GCL)
and barrier to autointegration factor (BAF) compete
for binding to emerin in vitro. J Biol Chem 278, 6969–
6975.
54 Dechat T, Korbei B, Vaughan OA, Vlcek S, Hutchison
CJ & Foisner R (2000) Lamina-associated polypeptide

J 274, doi:10.1111 ⁄ j.1742–4658.2007.05696.x
61 Melcon G, Kozlov S, Gutler DA, Sullivan T, Hernan-
dez L, Zhao P, Mitchell S, Nader G, Bakay M, Rott-
man JN et al. (2006) Loss of emerin at the nuclear
envelope disrupts the Rb1 ⁄ E2F and MyoD pathways
during muscle regeneration. Hum Mol Genet 15, 637–
651.
62 Bakay M, Wang Z, Melcon G, Schiltz L, Xuan J, Zhao
P, Sartorelli V, Seo J, Pegoraro E, Angelini C et al.
(2006) Nuclear envelope dystrophies show a transcrip-
tional fingerprint suggesting disruption of Rb-MyoD
pathways in muscle regeneration. Brain 129, 996–1013.
63 Somech R, Izraeli S & JS (2004) Histone deacetylase
inhibitors – a new tool to treat cancer. Cancer Treat
Rev 30, 461–472.
64 Peterson CL & Laniel MA (2004) Histones and histone
modifications. Curr Biol 14, R546–R551.
65 Santos-Rosa H & Caldas C (2005) Chromatin modifier
enzymes, the histone code and cancer. Eur J Cancer 41,
2381–2402.
66 Sadoni N, Langer S, Fauth C, Bernardi G, Cremer T,
Turner BM & Zink D (1999) Nuclear organization of
mammalian genomes. Polar chromosome territories
build up funcly distinct higher order compartments.
J Cell Biol 146, 1211–1226.
67 Capell BC & Collins FS (2006) Human laminopathies:
nuclei gone genetically awry. Nat Rev Genet 7, 940–952.
68 Burke B & Stewart CL (2002) Life at the edge: the
nuclear envelope and human disease. Nat Rev Mol Cell
Biol 3, 575–585.

type lamins regulate retinoblastoma protein function by
promoting subnuclear localization and preventing pro-
teasomal degradation. Proc Natl Acad Sci USA 101,
9677–9682.
75 Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K,
Debril MB, Miard S & Auwerx J (2002) The retinoblas-
toma-histone deacetylase 3 complex inhibits PPAR-
gamma and adipocyte differentiation. Dev Cell 3, 903–
910.
76 Sabatelli P, Lattanzi G, Ognibene A, Columbaro M,
Capanni C, Merlini L, Maraldi NM & Squarzoni S
(2001) Nuclear alterations in autosomal-dominant
Emery-Dreifuss muscular dystrophy. Muscle Nerve 24,
826–829.
77 Goldman RD, Shumaker DK, Erdos MR, Eriksson M,
Goldman AE, Gordon LB, Gruenbaum Y, Khuon S,
Mendez M, Varga R et al. (2004) Accumulation of
mutant lamin A causes progressive changes in nuclear
architecture in Hutchinson–Gilford progeria syndrome.
Proc Natl Acad Sci USA 101, 8963–8968.
78 Shumaker DK, Dechat T, Kolmaier A, Adam SA,
Bozovsky MR, Erdos MR, Eriksson M, Goldman AE,
Khuon S, Collins FS et al. (2006) Mutant nuclear lamin
A leads to progressive alterations of epigenetic control
in premature aging. Proc Natl Acad Sci USA 103, 8703–
8708.
79 Scaffidi P & Misteli T (2006) Lamin A-dependent
nuclear defects in human aging. Science 312, 1059–1063.
80 Scaffidi P & Misteli T (2005) Reversal of the cellular
phenotype in the premature aging disease Hutchinson–