“Life Science” field

Figure 1 : DNA folding structure

Achievement : Discovery of histone modifications as
fundamental regulators of gene expression

Dr. C. David Allis

2 nmDNA
histoneBorn: March 22, 1951 (Age 62)
Joy and Jack Fishman Professor
Head, Laboratory of Chromatin Biology and Epigenetics
The Rockefeller University

Summary
A human body consists of approximately 60 trillion cells, and mostof them have the same genetic information in DNA (deoxyribonucleicacid). How can cells with the same DNA develop into many different
types of cells to make up the different organs in the body withdifferent forms and functions, such as skin, liver and cranial nerves?
A biochemist from the U.S., Dr. David Allis, tackled this question anddiscovered from his research in the 1990s that enzymes that chemicallymodify histones, proteins found in chromosomes, play a vital role in
the regulation of gene activity. His findings have greatly contributed tothe understanding of the generation mechanism in which an organism
grows from a fertilized egg, as well as to the development of drugs totreat cancer related to abnormalities in histone modifications.

How do various organs result from cellswith the same genetic information?
DNA, which is found within the cell nucleus of living organisms, iscalled “the blueprint of life.” Ever since the double helical structureof DNA was discovered by James Watson and Francis Crick in 1953,
scientists have been endeavoring to explain how life phenomena arebrought about by means of the information written in the DNA. In
the 1990s, the Human Genome Project commenced with the goal of
decoding the entire base sequence (genome) of the human DNA andwas completed in 2003, 50 years after the discovery by Watson andCrick.
Is it possible to understand all about life phenomena if the base sequence of DNA is defined? Unfortunately, the answer is “no.” While
the Human Genome Project was in progress, it was becoming clear
that, in addition to the genetic information of the DNA, there exists
a mechanism in which a part of the genetic information is selectivelyexpressed at each cell level and that this system is extremely vital inlife phenomena.
For example, in the human body, there are approximately 300 typesof cells, and with the exception of a small fraction, most have the sameDNA. Despite having the same DNA, they develop into different
types of cells with different forms and functions, such as skin cells andhepatic cells. The characteristics of these cells carry on even after cell
division.
The academic field which studies chromosomes controllingmechanisms without changes in DNA sequences is called epigenetics. Epigenetics has several research themes, such as a phenomenon
known as “DNA methylation.” Dr. David Allis was the first to clarify
in 1996 that a chemical modification known as acetylation occurs on
histones, proteins which constitute the chromosomes in eukaryotes(organisms having a nucleus within the cell), and that such modifications are relevant to the controlling of gene expression. His discovery
has made a significant contribution to the development of the emerging
science of epigenetics.

Fascinated by Real Lab's appeal, taking on the challenge ofthe mechanism of the genetic expression control
Dr. Allis was born in Cincinnati, a major city in southwestern
Ohio, the United States, in 1951. After graduating from high school,
he entered the University of Cincinnati. He majored in biology inpreparation for medical school. However, his advisor suggestedthat he experience basic research (Dr. Allis refers to this as the RealLab), which is another forefront indispensable to the development ofmedicine. He ended up becoming engrossed with this basic research,in particular embryology, and acquired a doctorate degree in biology

11 nm
nucleosome

30 nm

chromatin structure

chromosome

DNA which extends to 2
meters in length whenstretched out, wraps
itself around proteins
called histones to form anucleosome.
Nucleosomes are further
arranged in a stacked
helical complex to form astructure called
chromatin, which isorganized to form achromosome.

at the postgraduate school of the University of Indiana in 1978.
He then moved on to the University of Rochester and made theUniversity of Virginia Health System his research base. There,
he conducted research on the functions of chromosomes using
various organisms such as drosophila, but eventually focused his
research subject on a unicellular organism called tetrahymena. The
cell nucleus of tetrahymena is divided into a micronucleus and amacronucleus. The micronucleus is not active normally, but carries
on through cell division similar to a reproductive cell of a higherorganism, and cell activity is carried on based on the DNA of themacronucleus.
In the 1990s, Dr. Allis chose histones, proteins that constitutethe chromosomes of tetrahymena, as the essential study theme of
his research group. What, then, is a histone? The DNA in our cells
becomes approximately two meters in length when stretched out.
Histones organize “long strands” of DNA into a cell nucleus just 10
micrometers in diameter in a compact and orderly fashion. DNA
coils itself around granular histones approximately two times toform a nucleosome. Nucleosomes are further arranged in a stacked
helical complex to form a structure called chromatin, which isorganized to form a chromosome (Figure 1).
What the researchers particularly paid attention about histones
was that the region within the DNA which is not used in cell activity
is bound strongly to histones. Conversely, when the base sequence
information is being used, the DNA distances itself from histones,
in a loosely unbound state. What substance regulates the bond
between the DNA and histones? Dr. Allis’ research team continued
to undertake the challenge of clarifying the difference between
chemical modifications in the macronucleus and the suspended
action in the micronucleus when tetrahymena is active.
There proved to be stiff competition developing among researchgroups worldwide. Finally, in 1996, it was clarified that with histonesin the region where genetic information could be read, histone
acetyltransferase which binds itself to the acetyl group is active. In
addition, through the balance between the histone acetyltransferase
and the histone deacetylase, genetic expression is regulated, thus
proving for the first time that changes in the chromatin structure
through histone modifications are actually regulating gene activity.

Study of histone modifications contributes to thedevelopment of next-generation medicine
The discovery by Dr. Allis’ research group served as a catalyst forthe rapid development of studies related to chromosome functions.

Figure 2 : Histone tails and acetylation
acetylation

histones

deacetylation（ in DNA can be read. ）（in DNA can not be read.）

Information storedAc

K9

Ac

K14

Information stored

Ac

Ac

Ac

Ac

K18

K23

K16

K5

K8
Ac

Ac

Ac

K56
H3H4H2A
H3Ac

K12

H2B

H4acetyl groupHistones form a structure known as a histone octamer in which eight small
proteins are bound together. Several proteins have a tail, and when anacetyl group is attached to the tail, DNA binding to histones is regulated.

It also clarified that not only the acetyl group but several othersubstances such as the methyl group also attach themselves tohistones (chemical modification). When probing into the histone
structure, there are eight small ball-like proteins connected together
in a form called a histone octamer, with some proteins having a “tail”
extension. A “histone code hypothesis,” in which it is thought thatmultiple chemical modification patterns connected to the tail function
as a “code,” controlling the gene expression, has been proposed, andstudies thereof are ongoing (Figure 2).
Dr. Allis’ research is also contributing to the progress of medicine.
For example, it has come to light that not only gene abnormalities
but also abnormalities in epigenetics such as histone modifications
contribute to the occurrence of cancer. There has been one report
after another of histone acetylation decrease in certain types ofcancer, and molecular-target drug named HDI (histone deacetylaseinhibitor) which repairs the balance between histone acetylase andhistone deacetylase has been proposed. With “Vorinostat,” the first
HID for cutaneous T-cell lymphoma approved in the U.S. in 2006,
studies of several new drug candidates are underway.
In addition, histone modifications play a major role in governing
the occurrence of organisms, contributing to the progress of regenerative medicine using iPS cells. The research into histone chemical
modifications pioneered by Dr. Allis, will continue to be a vital fieldin the future development of life science.