Stowers Institute's Workman Lab discovers novel histone demethylase protein complex

December 08, 2008

The Stowers Institute's Workman Lab has discovered a novel histone demethylase protein complex characterized in work published today in Molecular Cell.

The Histone H3 protein is an important component of chromatin, the packing material wrapping up chromosomal DNA and preventing unwanted transcription of the message encoded in the DNA. Histone H3 can be altered by adding (methylating) or removing (demethylating) methyl groups from the histone protein. When genes are transcribed, parts of chromosomes are opened, making them susceptible to inappropriate use. Cells mark transcribed regions of chromosomes with a "landmark," called H3 lysine 36 methylation (H3K36), to direct appropriate use.

Working in fruit flies, the Workman Lab investigated how cells direct dKDM4A, a novel histone demethylase protein, to specific locations, which is important because dKDM4A is responsible for removal of landmark histone modifications during transcription elongation.

"We discovered that dKDM4A can remove specific forms of H3K36, reversing methylation and helping to regulate transcription elongation," said Chia-Hui Lin, Predoctoral Researcher and lead author on the paper. "Surprisingly, we found that dKDM4a associates with Heterochromatin Protein 1a (HP1a), a classic transcriptional silencing factor. The binding of HP1a stimulates the histone demethylation activity of dKDM4A. In fruit fly larvae without HP1a, we found a significantly increased level of H3K36."

"It is known that HP1a acts as a 'scaffold' component during transcription silencing, but recent findings of HP1a's involvement in actively transcribed regions had confounded the chromatin field," said Jerry Workman, Ph.D., Investigator and senior author on the paper. "This work suggests a possible role for HP1a in transcription activation by facilitating histone demethylation by dKDM4A to remove an important histone mark during elongation."

The discovery applies to human health especially as it relates to Huntington disease. The human enzyme that adds methylation marks on histone H3K36 interacts with the Huntington protein, which causes Huntington's disease. Additionally, the human version of dKDM4A functions as an oncogene, which has the potential to cause a normal cell to become cancerous. Overexpression of such a gene product can lead to esophageal squamous carcinoma and prostate cancer. The Workman Lab's efforts to learn more about the dynamic regulation of H3K36 methylation may lead to the discovery of potential mechanisms to cure or alleviate these diseases.

Stowers Institute for Medical Research

Nutrients and Epigenetics
by Sang-Woon Choi (Editor), Simonetta Friso (Editor)

Explores the Newly Discovered Link Between Nutrition and Epigenetics Current research suggests that nutrients are more than just food components and that certain nutrients can impact the expression of genes that lead to the development of chronic diseases. With contributions from experts in both fields, Nutrients and Epigenetics examines the epigenetic phenomena and the fascinating implications of diet on this largely uncharted field. Generously laden with tables and illustrations, many in color, this book addresses how nutrients alter physiologic and pathologic processes in the human body through epigenetic changes without affecting the DNA sequence. It also explains the detailed molecular structures of epigenetic phenomena and closely examines the current knowledge surrounding...

Histone Deacetylases: Transcriptional Regulation and Other Cellular Functions (Cancer Drug Discovery and Development)
by Eric Verdin (Editor)

A panel of leading investigators summarizes and synthesizes the new discoveries in the rapidly evolving field of histone acetylation as a key regulatory mechanism for gene expression. The authors describe what has been learned about these proteins, including the identification of the enzymes, the elucidation of the enzymatic mechanisms of action, and the identification of their substrates and their partners. They also review the structures that have been solved for a number of enzymes-both alone and in complex with small molecule inhibitors-and the biological roles of the several histone deacetylases (HDAC) genes that have been knocked out in mice.

Epigenetics in Biology and Medicine
by Manel Esteller (Editor)

Anomalous epigenetic patterns touch many areas of study including biomedical, scientific, and industrial. With perspectives from international experts, this resource offers an all-inclusive overview of epigenetics, which bridge DNA information and function by regulating gene expression without modifying the DNA sequence itself. Epigenetics, in its most basic form, means heredity is not the sole determining factor in disease development. Rather, environmental and dietary factors can trigger a gene to behave in an unintended way, while the gene itself remains unchanged. Epigenetics in Biology and Medicinediscusses cell biology and epigenetics’ role in human, animal, and plant diseases, including distortions in DNA methylation. The text also covers histone modifications, and...

Brain, Behavior and Epigenetics (Epigenetics and Human Health)
by Arturas Petronis (Editor), Jonathan Mill (Editor)

Biomedical research in the first decade of the 21st century has been marked by a rapidly growing interest in epigenetics. The reasons for this are numerous, but primarily it stems from the mounting realization that research programs focused solely on DNA sequence variation, despite their breadth and depth, are unlikely to address all fundamental aspects of human biology. Some questions are evident even to non-biologists. How does a single zygote develop into a complex multicellular organism composed of dozens of different tissues and hundreds of cell types, all genetically identical but performing very different functions? Why do monozygotic twins, despite their stunning external similarities, often exhibit significant differences in personality and predisposition to disease? If...

Chromatin and Disease (Subcellular Biochemistry)
by Tapas K. Kundu (Editor), Dipak Dasgupta (Editor)

This book includes a collection of articles with the broad theme of disease connection to chromatin structure and function. It elaborates on the molecular pharmacology of the drugs targeting chromatin structure and its components. The book contains up-to-date information about the chromatin structure and chromatin related diseases and drug functions. This work is the first endeavor to present different aspects encompassing the above theme.

RNA: Life's Indispensable Molecule
by James Darnell (Author)

In RNA: Life's Indispensable Molecule, Jim Darnell provides a comprehensive and captivating account of RNA research, illuminated by his own life-long and celebrated engagement in the field. Darnell describes how scientists unraveled fundamental questions about the biochemical and genetic importance of RNA, how mRNAs are generated and used to produce proteins, how noncoding and catalytic RNAs mediate key cellular processes, and how RNA molecules likely initiated life on Earth. With a scope extending from the early 20th century to the present day, and with the clarity expected from an accomplished textbook author, he conveys the intellectual context in which these questions first arose and explains how the key experiments were structured and answers obtained. The book is geared towards...

Cancer Epigenetics
by Trygve Tollefsbol (Editor)

During the past few decades, it has become increasingly apparent that heredity is not the sole determining factor in disease development, such as cancer. This landmark work covers a wide array of aspects in the relatively new area of epigenetics, ranging from its role in the basic mechanisms of tumorigenesis, to the newest epigenetic drugs being developed and used for cancer therapy. Cancer Epigenetics presents in-depth discussions of DNA methylation alterations, histone and RNA modifications, and nucleosome remodeling, which are all intimately involved in the formation of tumors. It also analyzes metabolic influences on cancer epigenetics and advances in epigenetic cancer gene therapy. Discusses the Latest Advances in the Role of Epigenetics in Tumor Initiation, Progression, and...

Chromatin Dynamics in Cellular Function (Results and Problems in Cell Differentiation)
by Brehon Laurent (Editor)

This volume includes timely reviews of several aspects of chromatin biology written by scientists at the forefront of this rapidly moving field. Topics covered include the structure and function of protein modules within chromatin-remodeling proteins, newly characterized histone modifications (methylation, ubiquitylation) and their functional consequences, transcription and histone dynamics, roles of chromatin remodeling factors in DNA replication and repair, and current models of nucleosome-remodeling mechanisms.

Sperm Chromatin: Biological and Clinical Applications in Male Infertility and Assisted Reproduction
by Armand Zini (Editor), Ashok Agarwal (Editor)

Sperm DNA damage is common and has been associated with reduced rates of conception, impaired embryonic development and increased risk of miscarriage. Although the exact causes of sperm DNA damage are unknown, it is clear that infertile men possess substantially higher levels of sperm DNA damage than do fertile men. Written by leading, internationally renowned clinicians and basic scientists with expertise in sperm DNA, Sperm Chromatin: Biological and Clinical Applications in Male Infertility and Assisted Reproduction provides readers with a thoughtful and comprehensive review of the biological and clinical significance of sperm DNA damage. The work covers the fundamental principles of sperm chromatin architecture and function, the proposed modes of DNA damage and repair, the tests of...

Handbook of Epigenetics: The New Molecular and Medical Genetics
by Trygve Tollefsbol (Editor)

Epigenetics is considered by many to be the "new genetics" because the realization that many biological phenomena are controlled not through gene mutations, but rather through reversible and heritable epigenetic processes that have opened up new paths for discovery. The biological processes impacted by epigenetics range from tissue/organ regeneration, X-chromosome inactivation, and stem cell differentiation to genomic imprinting and aging. The effects of epigenetics are vast and encompass lower organisms as well as humans. Aberrations of epigenetics influence many diseases involving but not limited to cancer, immune disorders, neurological and metabolic disorders, and imprinting diseases. Clinical intervention is already in place for some of these disorders and many novel epigenetic...