Genome Organization Inside the Nucleus

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urnal of Mo
l
Jo
ed
tic M icine
ne
ular and Ge
ec
ISSN: 1747-0862
Journal of Molecular and Genetic
Medicine
Research
Commentary Article
Khanna, J Mol Genet Med 2016, 10:4
DOI: 10.4172/1747-0862.1000239
Open
Access
OMICS
International
Genome Organization Inside the Nucleus
Khanna N*
Division of Biological Sciences, University of California, San Diego, USA
Summary
The mammalian cell nucleus is organized in a highly-ordered
manner. Within nucleus, the genetic loci occupy preferential location
[1-4]. For instance, some gene loci are present at nuclear periphery;
some other gene loci interact with nuclear bodies such as nucleoli,
nuclear speckles, Cajal bodies, etc. [5]. This preferential localization of
gene loci varies depending on cell type or physiological conditions.
Discussion and Conclusion
Increasing evidence suggests a role of spatial localization of genetic
material in influencing genome function. Several developmentally
regulated genes are present at the nuclear periphery when they are
inactive but reposition to the nuclear interior when they are active [6,7].
For example, immunoglobulin heavy chain (IgH) locus is located at the
nuclear periphery when it is inactive, during the developmental stage.
Whereas, when IgH gene is active, it is present in the nuclear interior
[6]. There are also examples of gene loci changing their association
with other nuclear bodies correlating with changes in transcription,
e.g. heat shock genes associated with nuclear speckles upon activation
by heat shock [8,9]. In addition, there are several descriptions where
co-regulated genes cluster within the nuclear space, e.g. co-expressed
erythroid genes were shown to cluster around nuclear speckles [10].
The molecular mechanism that governs the organization of
genome is an active area of research. Some of the recent findings show
that chromatin modifiers or epigenetic marks are responsible for the
specific localization of a few genetic loci, e.g. histone H3K9 di and trimethylation by histone methyltransferase are required to localize some
gene loci to nuclear periphery [11-14].
The disruption in the spatial organization of the genome has been
identified in multiple human diseases. Chromosomal translocations,
which are common in various cancers, are proposed to preferentially
occur between chromosomes occupying nearby space in the nucleus
[15]. In a variety of diseases, there are examples where individual
genes, larger genomic segments or whole chromosomes change their
localization [16,17]. Additionally, several proteins involved in the
higher order organization of the genome are also implicated in diseases
[18-20]. The most prominent are laminopathies, which are a group of
diseases caused by mutations in nuclear envelope (NE) proteins. For
example, mutations in lamin A/C causes Emery-Dreifuss muscular
dystrophy (EDMD) and premature aging disease Hutchison-Gilford
progeria syndrome (HGPS) [20-22].
With the help of advanced approaches like Chromosome
conformation capture techniques (also known as 3C based techniques),
DNA adenine methyltransferase identification (DamID), and
microscopy; nuclear organization of genome is mapped at a greater
depth [23-27]. Mapping of the genome organization across different cell
types, development stages, and various physiological conditions will
help us to better understand the role genome organization in genome
function. In depth knowledge of genome organization along with
genome editing tools can help towards better diagnosis and treatment
of diseases.
Over the years, spatial organization of genetic material inside nucleus
J Mol Genet Med, an open access journal
ISSN: 1747-0862
has been shown to be critical for genomic functions and its disruption
has been linked to diseases. Although poorly understood, the recent
advancement of technologies holds a promising future towards mapping the genome organization to a greater detail and understanding the
underlying molecular mechanisms.
The mammalian cell nucleus is organized in a highly-ordered
manner. It is compartmentalized into chromosome territories along
with many distinct nuclear bodies such as speckles, nucleoli, Cajal
bodies among others [1-5]. Within nucleus, the genetic loci occupy
preferential location. For instance, some gene loci are present at nuclear
periphery; some other gene loci interact with nuclear bodies [6]. This
preferential localization of gene loci varies depending on cell type or
physiological conditions [7,8].
Increasing evidence suggests a role of spatial localization of
genetic material in influencing its function. Several genes that change
their nuclear location during cellular development also change their
expression status [9,10]. For example, during lymphocyte development,
immunoglobulin heavy chain (IgH) locus is located at the nuclear
periphery when it is inactive. Whereas, when IgH gene is active, it is
present in the nuclear interior [9]. There are also examples of gene
loci changing their association with other nuclear bodies correlating
with changes in transcription, such as heat shock genes associate with
nuclear speckles upon activation by heat shock [11,12]. In addition,
there are several descriptions where co-regulated genes cluster within
the nuclear space, for instance coexpressed erythroid genes have been
shown to cluster around nuclear speckles [13].
The molecular mechanism that governs the organization of genome
is an active area of research. Some of the recent findings show that
chromatin modifiers or epigenetic marks are responsible for the specific
localization of a few genetic loci. For example, histone H3K9 di and trimethylation by histone methyltransferase are required to localize some
gene loci to nuclear periphery [14-17].
Disruption in the spatial organization of genome has been identified
in multiple human diseases. Chromosomal translocations, which
are common in various cancers, are proposed to preferentially occur
between chromosomes occupying nearby space in the nucleus [18]. For
example, chromosomes 12 and 16 that are frequently translocated in
liposarcoma patients are also found in close proximity in differentiated
adipocytes [19]. In a variety of diseases, there are examples where
individual genes, larger genomic segments or whole chromosomes
change their localization [20,21]. Additionally, several proteins involved
*Corresponding author: Dr. Nimish Khanna, Division of Biological Sciences,
University of California, San Diego, USA, Tel: 18585342230; E-mail:
[email protected]
Received November 14, 2016; Accepted December 28, 2016; Published December
30, 2016
Citation: Khanna N (2016) Genome Organization Inside the Nucleus. J Mol Genet
Med 10: 239 doi:10.4172/1747-0862.1000239
Copyright: © 2016 Khanna N. This is an open-access article distributed under the
terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited
Volume 10 • Issue 4 • 1000239
Citation: Khanna N (2016) Genome Organization Inside the Nucleus. J Mol Genet Med 10: 239 doi:10.4172/1747-0862.1000239
Page 2 of 2
in the higher order organization of the genome are also implicated in
diseases [22-24]. The most prominent of these are laminopathies, which
are a group of diseases caused by mutations in nuclear envelope (NE)
proteins. For example, mutations in lamin A/C cause Emery-Dreifuss
muscular dystrophy (EDMD) and premature aging disease HutchisonGilford progeria syndrome (HGPS) [25-27].
With the help of advanced approaches like Chromosome
conformation capture techniques (also known as 3C based techniques),
DNA adenine methyltransferase identification (DamID), and
microscopy; nuclear organization of genome is mapped at a greater
depth [28-33]. Mapping of the genome organization across different cell
types, development stages, and various physiological conditions will
help us to better understand the role genome organization in genome
function. In depth knowledge of genome organization along with
genome editing tools can help towards better diagnosis and treatment
of diseases.
References
1. Misteli T (2007) Beyond the sequence: Cellular organization of genome
function. Cell 128: 787-800.
2. Cremer T, Cremer C (2001) Chromosome territories, nuclear architecture and
gene regulation in mammalian cells. Nat Rev Genet 2(4): 292-301.
3. Sexton T, Schober H, Fraser P, Gasser SM (2007) Gene regulation through
nuclear organization. Nat Struct Mol Biol 14: 1049-1055.
4. Meaburn KJ, Burman B, Misteli T (2016) Spatial genome organization and
disease. The Functional Nucleus 1: 101-125.
5. Meaburn KJ (2016) Spatial genome organization and its emerging role as a
potential diagnosis tool. ECollection 7: 134.
6. Bickmore WA, Van Steensel B (2013) Genome architecture: Domain
organization of interphase chromosomes. Cell 152(6): 1270–1284.
7. Parada L, McQueen P, Misteli T (2004) Tissue-specific spatial organization of
genomes. Genome Biol 7: R44.
8. Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, et al. (2014)
A 3D map of the human genome at kilobase resolution reveals principles of
chromatin looping. Cell 159: 1665–1680.
9. Kosak ST, Skok JA, Medina KL, Riblet R, Le-Beau MM, et al. (2002) Subnuclear
compartmentalization of immunoglobulin loci during lymphocyte development.
Science 296 (5565): 158–162.
10.Williams RR, Azuara V, Perry P, Sauer S, Dvorkina M, et al. (2006) Neural
induction promotes large-scale chromatin reorganisation of the Mash-1 locus.
J Cell Sci 119: 132–140.
14.Zullo JM, Demarco IA, Pique-Regi R, Gaffney DJ, Epstein CB, et al. (2012)
DNA sequence-dependent compartmentalization and silencing of chromatin at
the nuclear lamina. Cell 149(7): 1474–1487.
15.Kind J, Pagie L, Ortabozkoyun H, Boyle S, De Vries SS, et al. (2013) Single-cell
dynamics of genome-nuclear lamina interactions. Cell 153(1): 178–192.
16.Towbin BD, Gonzalez-Aguilera C, Sack R, Gaidatzis D, Kalck V, et al. (2012)
Step-wise methylation of histone H3K9 positions heterochromatin at the
nuclear periphery. Cell 150(5): 934–947.
17.Bian Q, Khanna N, Alvikas J, Belmont AS (2013) Beta-globin Cis-elements
determine differential nuclear targeting through epigenetic modifications. J Cell
Biol 203(5): 767–783.
18.Bickmore WA, Teague P (2002) Influences of chromosome size, gene density
and nuclear position on the frequency of constitutional translocations in the
human population. Chromosome Res 10 (8): 707–715.
19.Kuroda M, Tanabe H, Yoshida K, Oikawa K, Saito A, et al. (2004) Alteration
of chromosome positioning during adipocyte differentiation. J Cell Sci 117:
5897–5903.
20.Reddy KL, Andrew P (2013) Feinberg higher order chromatin organization in
cancer. Semin Cancer Biol 23(2): 109-115.
21.Karen J, Meaburn D (2016) Spatial genome organization and its emerging role
as a potential diagnosis tool. Front Genet 7:134.
22.Misteli T (2010) Higher-order genome organization in human disease. Cold
Spring Harb Perspect Biol 2(8): a000794.
23.Woodcock CL (2006) Chromatin architecture. Curr Opin Struct Biol 16:
213–220.
24.Hock R, Furusawa T, Ueda T, Bustin M (2007) HMG chromosomal proteins in
development and disease. Trends Cell Biol 17: 72–79.
25.Ellis JA, Shackleton S (2011) Nuclear envelope disease and chromatin
organization. Biochem Soc Trans 39: 1683–1686.
26.Dittmer TA, Misteli T (2011) The lamin protein family. Genome Biol 12(5): 222.
27.Burke B, Stewart CL (2013) The nuclear lamins: Flexibility in function. Nat Rev
Mol Cell Biol 14(1): 13–24.
28.Steensel VB, Dekker J (2010) Genomics tools for unraveling chromosome
architecture. Nat Biotechnol 28(10): 1089–1095.
29.Guelen L, Pagie L, Brasset E, Meuleman W, Faza MB, et al. (2008) Domain
organization of human chromosomes revealed by mapping of nuclear lamina
interactions. Nature 453(7197): 948–951.
30.Khanna N, Bian Q, Plutz M, Belmont AS (2013) BAC manipulations for making
BAC transgene arrays. Methods Mol Biol 1042: 197–210.
11.Hu Y, Kireev I, Plutz M, Ashourian N, Belmont AS (2009) Large-scale chromatin
structure of inducible genes: transcription on a condensed, linear template. J
Cell Biol 185: 87-100.
31.Mattout A, Cabianca DS, Gasser SM (2015) Chromatin states and nuclear
organization in development: A view from the nuclear lamina. Genome Biology
16: 174.
12.Khanna N, Hu Y, Belmont AS (2014) HSP70 transgene directed motion to
nuclear speckles facilitates heat shock activation. Curr Biol 24(10): 1138–1144.
32.Belmont AS, Hu Y, Sinclair PB, Wu W, Bian Q, et al. (2010) Insights into
interphase largescale chromatin structure from analysis of engineered
chromosome regions. Cold Spring Harb Symp Quant Biol 75: 453–460.
13.Brown JM, Green J, Das Neves RP, Wallace HA, Smith AJ, et al. (2008)
Association between active genes occurs at nuclear speckles and is modulated
by chromatin environment. J Cell Biol 182(6): 1083–1097.
33.Ramani V, Shendure J, Duan Z (2016) Understanding spatial genome organization:
Methods and insights. Genomics Proteomics Bioinformatics 14: 7–20.
Citation: Khanna N (2016) Genome Organization Inside the Nucleus. J Mol Genet
Med 10: 239 doi:10.4172/1747-0862.1000239
J Mol Genet Med, an open access journal
ISSN: 1747-0862
Volume 10 • Issue 4 • 1000239
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