Biology Reference
In-Depth Information
Chapter 7
The Spatial Architecture of Chromosomes
Job Dekker
1
and Bas van Steensel
2
1
Program in Systems Biology and Program in Gene Function and Expression, Department of Biochemistry and Molecular Pharmacology, University
of Massachusetts Medical School, Worcester, MA, USA,
2
Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, the Netherlands
Chapter Outline
Introduction
137
The Internal Organization of Chromosomes: Long-Range
Interactions Along and Between Chromosomes
The Basic Material: the Chromatin Fiber
139
145
The Polymer Physics of Chromosomes
139
Molecular Techniques to Map Long-Range Chromatin
Interactions
Persistence Length
140
146
Mass Density
140
Determination of Polymer Parameters using 3C Chromatin
Interaction Data
Polymer States
140
146
The Ground State of an Unconstrained Chromosome
141
Co-association of Large Active and Inactive Chromosomal
Domains leads to Chromosome Compartmentalization
Polymer Conformation is Probabilistic
141
147
Nuclear Confinement and Formation of Chromosome
Territories
Looping Interactions between Genomic Elements to
Regulate Genes
141
147
Anchoring of the Genome to Fixed Scaffolds
142
A Dynamic Network View of Chromosome Folding
148
Genome-Wide Techniques to Map Scaffold Interactions
142
A Stochastic Interaction-Driven Model for Genome Folding
and Nuclear Organization
Nuclear Lamina
e
Genome Interactions in Metazoans
143
148
Gene Attachment to Nuclear Pores
144
Future Challenges
149
The Nucleolus as a Spatial Organizer
145
References
149
INTRODUCTION
A human diploid cell nucleus contains 46 chromosomes,
each harboring one DNA double helix. If stretched out,
these DNA molecules would each be 1.5
disappearance in interphase. Based on careful observation
of the segregation patterns of chromosomes during meiosis,
Sutton and Boveri subsequently concluded that chromo-
somes must be the carriers of the genetic information,
several years before Morgan confirmed this by genetic
studies in Drosophila and decades before the classic
experiments by Avery that experimentally demonstrated
that DNA is the genetic material.
For more than 100 years, microscopy remained the
prime technique to study chromosome architecture and
dynamics, but the dense packing of the chromatin fiber has
made it difficult to resolve structural features. Electron
microscopy allowed initial studies of chromosome folding,
e.g., as described in early work by DuPraw
[1]
. A major
breakthrough was the development of fluorescence in situ
hybridization (FISH), which allowed the visualization of
individual sequences or entire chromosomes inside the
nucleus
[2]
. Such FISH studies have provided firm
evidence that interphase chromosomes are not completely
diffuse
8 cm long, yet
a typical human nucleus has a diameter of only 5
e
m.
Therefore, DNA must be extensively folded within the
confines of the nucleus, resulting in roughly 10 000-fold
compaction. At the same time, genes, regulatory elements
and other genomic information are spread out across the
6 billion base pairs, but these elements must communicate
appropriately, which often involves direct physical contacts,
to ensure normal gene expression. Moreover, at every cell
division all chromosomes are copied and the resulting
duplicates are faithfully separated from one another. How is
this remarkable topological feat accomplished?
Interphase chromatin and mitotic chromosomes were
first described in the late 1800s. Using early light micro-
scopes, Flemming was the first to observe compacted
chromosomes and their dramatic changes in morphology
during their formation in prophase and their apparent
10
m
e
and non-randomly organized,
as
the
early
