熊本大学発生医学研究所／ P05-06 【英訳】Division of Developmental Regulation

Medical Cell Biology“Focus on EPIgenetics”
Understanding how our life anddisease are programmed
Applying new findings to future medicine
Our body and mind function through gene control on the genome.
Epigenetics is the study of the “program of life.”
Changes in this program can lead to cancer, lifestyle disease, and aging.
Epigenetics: advanced research focused on the essence of life and disease

Epigenetics: mechanisms forregulating gene activity
Genome is the blueprint of our life. Human bodies are
made up of more than 200 types of cells, and each ofthese cells contains, in principle, the same genome. So
why is that, despite the genome being the identical,
each cell is so distinctly unique? As Professor Nakaoputs it, “There are around 25,000 genes in the humangenome, of which about 10,000 genes are active in asingle cell. The individual cell does not use theremaining genes. Essentially what this means is thatgenes are used selectively. The program—in otherwords, the selective use of genes—differs according to
the cell type and the cell condition. This is what enablesus to live every day.” He explains further: “To control
the gene activity in the human genome, each gene isgiven marks. The epigenome is the modified genome
where all genes are distinctively marked, and theepigenetics is the study of the biological significance ofthe epigenome. Put simply, epigenetic research tries tounderstand how gene activity is regulated in our lifeand disease.”

Deciphering the epigenome:
benefits for future medicine andhealthcare
So what exactly are the “marks” on the epigenome?
Marks are made either by DNA methylation or byhistone modification, by complexes of DNA andprotein (known as chromatin) or by intranuclear

structure in the cell. The epigenome, actually, consistsof many numbers of molecules binding with andmarking the genome; stem cells, differentiated cells,
cancer cells, and senescent cells all have their own
distinct epigenome. “It has been established that
epigenetic mechanisms determine how each gene is tobe activated or to be inactivated in individual cell, andthese cells together make up our body. On the otherhand, in germ cells, this marking is temporarily erased,
then to be rewritten with a parental origin-specificmark in the mother or the father. It’s a very amazing
mechanism.”
By examining the markings on the epigenome, we canknow the nature of the cell. Dr. Nakao notes this ability
to diagnose the “identity" of each cell has allowed us tomake important discoveries for regenerative medicine,cancer therapies, and reproductive treatments.

Epigenetic memory induced bylife style and dietIn recent years, it has been reported that the epigenome
can be affected by environmental factors such as dietand nutrition. The increasing researches focus on thelinks between the epigenome and lifestyle disease. AsDr. Nakao says, “It is quite evident that the marks on
the epigenome may be affected by diet, exercise, andthe environment in which we are brought up and areliving every day. The marks on the epigenome change,
and these changes will be maintained for a long time.
This is what we refer to as ‘epigenetic memory’ .”A set of identical twins, for example, both came fromthe same fertilized egg, so they have exactly the samegenome. After they grow older, they may become quitedifferent. The greater the difference in life style andliving environment, the more clear dissimilarities mayemerge between the twins. “The more identical twins
age, the greater the differences in DNA methylationand histone modification will appear. This has been
made clear by research. Essentially, what theyaccumulate every day comes to affect their epigenomes.
For example, we have found that, in the case of high fat
diet–induced obesity, a new epigenetic mechanism byLSD1 is involved in the reprogram to store excessiveenergy.”
All cancer cells have epigenetic abnormalities such ast he cha nges of DNA met hylation, a nd t hese
abnormalities are useful for the cell diagnosis. It would
perhaps not be an exaggeration to say that humandisease is caused by errors in the epigenetic programand epigenetic memory. Epigenetics research seeks touncover the foundation of life and disease, andcontributes to understanding the mechanism of the iPS
cell induction and the production of the desired
cells/tissues, and the pathogenesis of cancer andlifestyle disease. “This is a research field that willcapture attention as we proceed further in the 21stcentury. There is so much potential to advance future
medicine and new drug development.”

Professor

Mitsuyoshi Nakao
mnakao@gpo.kumamoto-u.ac.jp

Profile1985 Graduates from the School of Medicine, Shimane Medical University
1991 Receives Ph. D. from the Graduate School of Medicine, Kurume University
1992 Research associate, Howard Hughes Medical Institute, Baylor College ofMedicine, USA
1995 Assistant and Associate professor, School of Medicine,
Kumamoto University
2002 Professor, Institute of Molecular Embryology andGenetics (IMEG), Kumamoto University
2006-2008, 2010-2014 Director, IMEG, Kumamoto University

Epigenetic regulation of biological processes

Higher-order epigenetic mechanisms

Epigenetic regulation of metabolism

Development

Cell proliferationand differentiation

Intranuclear structure

Basisof life
activities

Chromatin loop

Epigenome
MeMeMeRegeneration

Cells having the same genome
can be programed into different types

Epigenetic memory

Transcription factory

EE

Nucleolus
Nuclear speckles
PML body

Energy metabolism

HP1 andhistone
methylation

CancerLifestyle disease
AgingmCpG

Health status

CTCF

MBD
KaisoES Heterochromatin

SecondarystructurePrimary structure

Nutrient
Metabolite
ChemicalMe

Gene activation

Gene inactivation

DNA methylation andhistone modification

PAc

mCpG

Fertilized egg

Heredity

Enhancer

Suppressor

Tissue and organ formation

Intranuclear
positioning

Tertiary structure

Phosphorylation
Acetylation

ATP
Acetyl-CoA

Methylation

SAM

Deacetylation

Lifestyle disease

CancerInflammation
andallergy

Mental andneurologicaldisorderDemethylation

+NAD

FAD
αketoglutarate

References●Hino S, Sakamoto A, Nagaoka K, Anan K, Wang Y,
Mimasu S, Umehara T, Yokoyama S, Kosai K, andNakao M. FAD-dependent lysine demethylase LSD1
regulates cellular energy expenditure. Nature Commun.
3: Article number 758, 2012.
●Hirosue A, Ishihara K, Tokunaga K, Watanabe T, Saitoh
N, Chandra T, Narita M, Shinohara M, and Nakao M.
Quantitative assessment of higher-order chromatin
structure of the INK4/ARF locus in human senescentcells. Aging Cell 11: 553-556, 2012.
●Watanabe T, Ishihara K, Hirosue A, Watanabe S, Hino
S , O j i m a H , K a n a i Y, S a s a k i Y, a n d N a k a o M .
Higher-order chromatin regulation and differential gene
expression in human tumor necrosis factor/lymphotoxin
locus in hepatocellular carcinoma cells. Mol. Cell. Biol.
32: 1529-1541, 2012.
●Saitoh N, Sakamoto C, Hagiwara M, Agredano-Moreno LT,
Jimenez-Garcia LF, and Nakao M. The distribution ofphosphorylated SR proteins and alternative splicing areregulated by RANBP2. Mol. Biol. Cell 23: 1115-1128, 2012.
●Mishiro T, Ishihara K, Hino S, Tsutsumi S, Aburatani H,Shirahige K, Kinoshita Y, and Nakao M. Architectural roles ofmultiple chromatin insulators at the human apolipoprotein
gene cluster. EMBO J. 28: 1234-1245, 2009.

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Teaching Staff
Associate Professor

Assistant Professor

Noriko Saitoh

Shinjiro Hino

Regulation of gene expression is important for almost all of
biological activities, including development, regeneration, anddiseases. My research focus is to understand how the cell
nucleus, as a three-dimensional structure, controls genes. I
would like to bring about a novel concept on geno meorganizations and functions. In IMEG, I would like to dedicate
myself to helping students who explore scientiﬁc ﬁeld, globally.

My research is focused on the mechanisms through which
environmental information, such as nutrition, is imprinted
onto cells and individuals. I examine, from a molecularlevel, the biological ﬂexibility that allows organisms to go
beyond their “default” program, and ultimately hope thatmy ﬁndings can form the basis of further useful work in
medicine and industry.

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