Biology

biology

The
Inner Life
of the
Genome

The way our genes are arrayed and move in the
3-D space of the cell nucleus turns out to profoundly influence
how they function, in both health and disease

By Tom Misteli

in brief

Chromosomes are not sprinkled
randomly around the inside
of the nucleus. They occupy
preferred positions.

This nuclear organization reflectsthe functional state of
each chromosome and of the
genes it carries. The organization
can change as a cell’s behavior
changes and in disease.

Identifying the locations that
genes occupy within the nucleus—
and seeing how these
positions change under different
conditions—is providing
clues to how normal cells function
and how some diseases,
including cancer, arise.

66Scientific American, February 2011

© 2011 Scientific American



Chromosomes in a dividing cell
(left) are duplicated and highly
compact. At other times, though,
they are singletons and more
expanded (below). Until the recent
advent of “chromosome painting”
techniques, the expanded
chromosomes were difficult to
distinguish from one another.

Illustrations by Anatomy Blue67

© 2011 Scientific American



Tom Misteli is a senior investigator at the National Cancer
Institute in Bethesda, Md. Aided by imaging tools he developed,
his laboratory is working to uncover fundamental principles of
three-dimensional genome organization in the nucleus of living
cells and to apply this knowledge to discovering new strategies
for addressing cancer and aging.68 Scientific American, February 2011

Ten years ago publication of the human genome
sequence gave the world a blueprint
for a human being. But just as a list of automobile
parts does not tell us how a car engine
works, the complete genome sequence—
a list of the DNA “letters” in all the chromosomes of
the human cell—did not reveal how the genome directs our
cells’ day-to-dayactivities or allows an individual to develop
from a fertilized egg into a functioning adult.

To better understand the way the genome as a whole orchestrates
the symphony of biological activity called life, I and others
in the new field of genome cell biology are examining how
chromosomes, and the genes they house, are arranged within
the three-dimensional space of the nucleus and howthat organization
influences their activities.

Aided by new 3-D imaging technology that allows us to peer
deeper than ever into the living cell, we have discovered a startlingly
vibrant ecosystem. In the nucleus, chromosomes physically
interact with neighboring chromosomes, genes on those
chromosomes migrate to different nuclear locations depending
on what they need to accomplish,and molecules that regulate
gene activity congregate in bustling hubs. These new discoveries
offer fresh insights into how our genomes maintain our
health and how some diseases, including certain cancers, arise;
they may also lead to new ways of diagnosing disease.

Early Questions

the recent progress grows out of discoveries made in the 1980s.
Back then, biologists knew thatchromosomes become highly
condensed during cell division, taking on the hourglass-shaped
structure that most of us picture when we think about the entities
that carry our genes from one generation to the next. They
also knew that chromosomes have a looser shape when cells
are not dividing and are going about their usual business. That
relaxed appearance made it hard to discern chromosomesindividually
even with the very best microscopes, and prevailing
opinion held that chromosomes in nondividing cells intermix
like spaghetti jumbled up in a bowl.

That view was prevalent in spite of some hints to the contrary.
In the early 1900s a German cell scientist named Theodor
Boveri
had objected to this “spaghetti
model” of chromosome organization.
Based on studies he had...