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Epigenetics, Early Development, and Adult Disease

By Laura Hall
June 2010

Trevor Archer, Ph.D.
Changes in the epigenetic mark pattern can "change the transcriptional potential across the entire genome," said Archer. (Photo courtesy of Steve McCaw)

Dorothy Duke
NIEHS Chief Grants Management Officer Dorothy Duke is a member of the NIH STEP Forum Organizing Committee. She was one of the organizers of this event. (Photo courtesy of Dorothy Duke)

DNA Methylation and Histone Modifications help to compartmentalize the genome into domains of different transcriptional potentials
In loosely packed euchromatin, left, transcription is active, whereas in tightly packed heterochromatin transcription is inactive. Green lines of DNA wrap around gray cylinders representing histone proteins. Black histone tails are modified where the blue, red, and yellow flags represent acetyl, methyl, and phosphate groups making up the putative histone "code." (Slide courtesy of Trevor Archer adapted from Jenuwein & Allis, Science 2001)

April 29, NIEHS Laboratory of Molecular Carcinogenesis (http://www.niehs.nih.gov/research/atniehs/labs/lmc/index.cfm) Chief Trevor Archer, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/lmc/cge/index.cfm), presented an introductory talk April 29 to enlighten an audience of both scientists and non-scientists about epigenetics and its role in disease. The talk was part of a Staff Training in Extramural Program (STEP) event at the NIH campus in Bethesda, Md., titled "Blast from the Past! Early Influences on Long-Term Health."

The forum focused on how epigenetic modification of gene expression, occurring during developmental periods in early life, can potentially affect long-term health and the issue of public health interventions.

As Archer explained, epigenetic changes in gene expression can be passed down through generations without changes in DNA sequence. The epigenetic change, which is often exposure induced, creates a phenotype or physical trait that does not follow the classical genetic inheritance rules of Mendel.

The epigenetic process can allow an induced change in gene expression that occurs in a grandmother to be inherited by her daughter or son as a fetus and influence the germ cells that will become her grandchildren.

Archer studies the structure and function of chromatin, which he defined as the combination of DNA and histone proteins that compacts and regulates the genetic material in each of our cells. "DNA can be made accessible for transcription, copying or repair by remodeling the compacted chromatin, altering the histone-DNA interactions within the chromatin subunits, called nucleosomes," he explained. "However, it is the epigenetic marks that signal if gene activation or silencing will occur."

The histone tails on chromatin can be modified by adding acetyl, methyl, or phosphate chemical groups. DNA can be modified by methyl groups. These modifications act like a code that gives stop and go signals for activating genes. Numerous enzymes and other proteins are involved. Archer categorized them as writers, readers, and erasers.

The writers modify histone by adding chemical groups, while readers are proteins with binding regions or motifs that recognize these modifications on DNA and histones. Erasers are enzymes that remove the modifications or marks, making these modifications reversible. This epigenetic code of marks on DNA and histone can promote or block gene transcription, thus affecting the proteins made as the downstream products of transcription.

Archer explained that the pattern of marks can be very complex, that multiple marks can occur with one nucleosome, and that there are multiple nucleosomes in each gene. These mark patterns change with development and cancer.

"Understanding how epigenetic information is deposited, maintained, and processed is key to understanding development and disease," said Archer. The ability to reprogram cells by reversing or adding epigenetic modifications has "profound implications for therapeutics," he added.

Archer's talk introduced topics covered by the other speakers at the forum.

Andrew Feinberg, M.D. (http://www.hopkinsmedicine.org/geneticmedicine/People/Faculty/Feinberg.html) Exit NIEHS, discussed how epigenetic control of tissue-specific developmental programming plays a role in common disease. Feinberg's genome-wide DNA methylation studies show that colon cancer cells acquire a mixed pattern of methylation, combining features of normal colon and several other tissue types. Feinberg said, "This form of epigenetic confusion lies at the heart of cancer." Key genes that regulate pattern formation and development had high levels of variability in their degree of DNA methylation, he explained, and that variability may explain disease.

Kjersti Aagaard-Tillery, M.D., Ph.D. (http://www.bcm.edu/obgyn/?pmid=11856) Exit NIEHS, studies fetal epigenetic changes that occur in the womb in response to maternal obesity and high-fat diet intake, maternal tobacco use, and environmental exposures. "Epigenetic alterations to the fetal genetic code reprogram expression of genes... [and] result in persistently altered risk of developing childhood and adult disease," she said.

Nancy Press, Ph.D. (http://www.ohsu.edu/xd/education/schools/school-of-nursing/faculty-staff/press_nancy_faculty_pg.cfm) Exit NIEHS, an anthropologist, spoke about the ethical, legal, and social implication (ELSI) considerations in epigenetic research. There are unintended effects of scientific findings in terms of cultural perceptions and policy implications, according to Press. Epigenetic research studies will benefit from an awareness of, and practice in investigating, these effects.

(Laura Hall is a biologist in the NIEHS Laboratory of Toxicology and Pharmacology currently on detail as a writer for the Environmental Factor.)

NIH STEP Forum on Epigenetics

All Department of Health and Human Services (HHS) employees were invited to the training forum, which was held at the Natcher Conference Center at the National Institutes of Health in Bethesda, Md. Many audience members participated through a live videocast, which was archived for DHHS employees at http://videocast.nih.gov/Summary.asp?File=15877 (http://videocast.nih.gov/Summary.asp?File=15877).

Screenshot of video

Video on the NIH website (http://videocast.nih.gov/Summary.asp?File=15877) Exit NIEHS

Speakers

Trevor Archer, Ph.D.
Chief, Laboratory of Molecular Carcinogenesis
National Institute of Environmental Health Sciences
"Introduction - Epigenetic Influences on Long-Term Health"

Andrew P. Feinberg, M.D.
Director, Center for Epigenetics
Chief, Division of Molecular Medicine
Johns Hopkins University School of Medicine, Baltimore, Md.
"The Epigenetic Basis of Common Human Disease"

Kjersti Aagaard-Tillery, M.D., Ph.D.
Assistant Professor Obstetrics and Gynecology
Baylor College of Medicine, Houston, Texas
"Developmental Origins of Adult Disease and Epigenetics: Programming the Fetal Epigenome"

Nancy Press, Ph.D.
Professor, School of Nursing and Department of Public Health, School of Medicine
Oregon Health and Science University, Portland, Ore.
"ELSI Perspectives on Epigenetics: A New Paradigm for Collaboration?"



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