Growth of new brain cells requires 'epigenetic' switch

January 09, 2009

New cells are born every day in the brain's hippocampus, but what controls this birth has remained a mystery. Reporting in the January 1 issue of Science, neuroscientists at the Johns Hopkins University School of Medicine have discovered that the birth of new cells, which depends on brain activity, also depends on a protein that is involved in changing epigenetic marks in the cell's genetic material.

"How is it that when you see someone you met ten years ago, you still recognize them? How do these transient events become long lasting in the brain, and what potential role does the birth of new neurons play in making these memories?" says Hongjun Song, Ph.D., an associate professor of neurology and member of the Johns Hopkins Institute of Cell Engineering's NeuroICE. "We really want to understand how daily life experiences trigger the birth and growth of new neurons, and make long-lasting changes in the brain."

The researchers reasoned that making long-term memories might require long-term changes in brain cells. And one type of cellular change that has long-lasting effects is so-called epigenetic change, which can alter a cell's DNA without changing its sequence but does change how and which genes are turned on or off. So they decided to look at the 40 to 50 genes known to be involved in epigenetics, and see if any of them are turned on in mouse brain cells that have been stimulated with electroconvulsive therapy-shock treatment. "It's long been known that ECT induces neurogenesis in rodents and humans, so we used it as our test case to find what is triggered downstream to cause new cells to grow," says Song.

One gene turned on in response to ECT was Gadd45b, a gene previously implicated in immune system function and misregulated in brain conditions like autism. To confirm Gadd45b is turned up in response to brain activity, the researchers also examined mice experiencing a different activity. Exposure to new surroundings, the team found, also turns on Gadd45b in brain cells.

To find out if Gadd45b is required for new brain-cell growth, the research team made mice lacking the Gadd45b gene and tested their ability to generate new brain cells after ECT. They injected the mice with a dye that marks new cells and three days after ECT examined the number of new cells containing that dye in brains from mice with and without the Gdd45b gene. They found that while normal brains showed a 140 percent increase in cell number after ECT, brains lacking Gadd45b only showed a 40 percent increase.

"The question then was, How does Gadd45b do this?" says Song. "It's been controversial that Gadd45b can promote epigenetic changes like global DNA demethylation, but we show that it can promote demethylation of certain genes."

The chemical methyl group, when attached to DNA near genes, can turn those genes off. This so-called epigenetic change is thought to silence genes a cell doesn't use.

By dissecting mature neurons from normal mouse brains and looking for the presence of methyl groups at certain genes known to promote cell growth, the researchers found that after ECT, these genes became demethylated.

However, doing the same thing with mice lacking Gadd45b resulted in no demethylation, suggesting to the team that Gadd45b is indeed required for demethylation.

"We're really excited about this-it's the first time we've seen dynamic epigenetic DNA changes in response to brain activity," says Song.

"Now that we have the mice lacking Gadd45b, our next goal is to see if these mice have problems with learning and memory and how Gadd45b specifically promotes the demethylation to lead to these long-term changes in the brain."

Johns Hopkins Medical Institutions

---

---

	Demethylation: Webster's Timeline History, 1932 - 2007 by Icon Group International (Author) Webster's bibliographic and event-based timelines are comprehensive in scope, covering virtually all topics, geographic locations and people. They do so from a linguistic point of view, and in the case of this book, the focus is on "Demethylation," including when used in literature (e.g. all authors that might have Demethylation in their name). As such, this book represents the largest compilation of timeline events associated with Demethylation when it is used in proper noun form. Webster's timelines cover bibliographic citations, patented inventions, as well as non-conventional and alternative meanings which capture ambiguities in usage. These furthermore cover all parts of speech (possessive, institutional usage, geographic usage) and contexts, including pop culture, the arts, social...
	Sterol demethylation inhibitor fungicides as disruptors of insect development and inducers of glutathione S-transferase activities in Mamestra ... Biochemistry and Physiology, Part C] by N.S. Johansen (Author), L.H. Moen (Author), E. Egaas (Author) This digital document is a journal article from Comparative Biochemistry and Physiology, Part C, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: To study physiological and biochemical effects of demethylation inhibitor (DMI) fungicides on non-target insects, larvae of the cabbage moth, Mamestra brassicae L., were exposed orally to propiconazole, (R,S)-1-[2-(2,4-diclophenyl)-4-propyl-1,3-dioolan-2-ylmetyl]-1H-1,2,4-triazole (100, 200 and 600 mg L^-^1) and fenpropimorph, (+/-)-cis-4-[3-(4-tert-butylphenyl)-2-methylpropyl] 2,6-dimethylmorpholinc (10, 100, 200 and 600 mg L^-^1) in a semi-synthetic diet. Ten mg L^-^1 of fenpropimorph...
	Copper-mediated oxidative DNA damage induced by eugenol: possible involvement of O-demethylation [An article from: Mut.Res.-Genetic Toxicology and Environmental Mutagenesis] by K. Sakano (Author), Y. Inagaki (Author), S. Oikawa (Author), Y. Hiraku (Author), Kawan (Author) This digital document is a journal article from Mut.Res.-Genetic Toxicology and Environmental Mutagenesis, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Eugenol used as a flavor has potential carcinogenicity. DNA adduct formation via 2,3-epoxidation pathway has been thought to be a major mechanism of DNA damage by carcinogenic allylbenzene analogs including eugenol. We examined whether eugenol can induce oxidative DNA damage in the presence of cytochrome P450 using [^3^2P]-5'-end-labeled DNA fragments obtained from human genes relevant to cancer. Eugenol induced Cu(II)-mediated DNA damage in the presence of cytochrome P450...
	Photocatalytic demethylation of 2,4,6-trinitrotoluene (TNT) by porphyrins [An article from: Chemosphere] by H.J. Harmon (Author) This digital document is a journal article from Chemosphere, published by Elsevier in 2006. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Illumination of tetraphenyl porphyrin sulfonate (TPPS), CuTPPs and FeTTPPS in solution with trinitrotoluene (TNT) at pH7 at room temperature using tungsten lamp illumination results in the degradation of TNT to yield trinitrobenzoic acid and trinitrobenzene. No other degradation products are observed. The rate of TNT degradation follows the series TPPS>FeTPPS>CuTPPS.
	Fish consumption and bioindicators of inorganic mercury exposure [An article from: Science of the Total Environment, The] by C.J.S. Passos (Author), D. Mergler (Author), M. Lemire (Author), M. Fillion (Author) This digital document is a journal article from Science of the Total Environment, The, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Background: The direct and close relationship between fish consumption and blood and hair mercury (Hg) levels is well known, but the influence of fish consumption on inorganic mercury in blood (B-IHg) and in urine (U-Hg) is unclear. Objective: Examine the relationship between fish consumption, total, inorganic and organic blood Hg levels and urinary Hg concentration. Methods: A cross-sectional study was carried out on 171 persons from 7 riparian communities on the Tapajos River (Brazilian...
	Environmental VOSCs--formation and degradation of dimethyl sulfide, methanethiol and related materials [An article from: Chemosphere] by R. Bentley (Author), T.G. Chasteen (Author) This digital document is a journal article from Chemosphere, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Volatile organic sulfur compounds (VOSCs) play a major role in the global sulfur cycle. Two components, dimethyl sulfide (DMS) and methanethiol (MT) are formed in large amounts by living systems (e.g. algae, bacteria, plants), particularly in marine environments. A major route to DMS is by action of a lyase enzyme on dimethylsulfoniopropionate (DMSP). DMSP has other roles, for instance as an osmoprotectant and cryoprotectant. Demethiolation of DMSP and other materials leads to MT. A major transport process is release of...
	Distribution of total and methyl mercury in sediments along Steamboat Creek (Nevada, USA) [An article from: Science of the Total Environment, The] by J. Stamenkovic (Author), M.S. Gustin (Author), M. Marvin-DiPasquale (Author) This digital document is a journal article from Science of the Total Environment, The, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: In the late 1800s, mills in the Washoe Lake area, Nevada, used elemental mercury to remove gold and silver from the ores of the Comstock deposit. Since that time, mercury contaminated waste has been distributed from Washoe Lake, down Steamboat Creek, and to the Truckee River. The creek has high mercury concentrations in both water and sediments, and continues to be a constant source of mercury to the Truckee River. The objective of this study was to determine concentrations of total and methyl...
	Anaerobic degradation of methoxylated aromatic compounds by Clostridium methoxybenzovorans and a nitrate-reducing bacterium Thauera sp. strain Cin3,4 ... Biodeterioration & Biodegradation] by T. Mechichi (Author), B.K.C. Patel (Author), S. Sayadi (Author) This digital document is a journal article from International Biodeterioration & Biodegradation, published by Elsevier in . The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: The coupling of growth of the o-demethylating bacterium, Clostridium methoxybenzovorans SR3, with a nitrate-reducing bacterium able to degrade aromatic compounds, Thauera sp. Cin3,4, allowed complete mineralization of poorly oxidizable methoxylated aromatic compounds such as vanillate, isovanillate, vanilline, anisate, ferulate and veratrate. C. methoxybenzovorans o-demethylated these aromatic compounds to their corresponding hydroxylated derivatives and fermented the side chains to acetate...
	Lead Optimization for Medicinal Chemists by Florencio Zaragoza Dörwald (Author) This book provides a wealth of information on how small structural modifications affect the pharmacokinetic properties of a compound, and thus gives rich, fact-based inspiration for the efficient development of new drugs. It is a valuable and compact reference guide for both medicinal chemists and graduate students in the pharmaceutical sciences.
	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...