New light on how Genes turn off and on

New insights into how genes turn on and off:

New insights into how genes turn on and off

New insights into how genes turn on and off

 

Researchers at UC Davis and the University of British Columbia have shed new light on methylation, a critical process that helps control how genes are expressed. Working with placentas, the team discovered that 37 percent of the placental genome has regions of lower methylation, called partially methylated domains (PMDs), in which gene expression is turned off. This differs from most human tissues, in which 70 percent of the genome is highly methylated.

While PMDs have been identified in cell lines, this is the first time they have been found in regular human tissue. In addition to enhancing our understanding of epigenetics, this work could influence cancer research and help illuminate how environmental toxins affect fetal development. .

Since it was unraveled more than ten years ago, the human genome has been the focus of both popular interest and intense scientific focus. But the genome doesn’t act alone; there are many factors that influence whether genes are turned on or off. One of these is an epigenetic process called methylation, in which a group of carbon and hydrogen atoms (a methyl group) attaches to DNA, adjusting how genes are expressed.

“I like to think of epigenetics as a layer on top of your genetic code,” said senior author Janine LaSalle, professor of medical microbiology and immunology. “It’s not the DNA sequence but it layers on top of that — and methylation is the first layer. Those layers provide a lot of information to the cells on where and when to turn on the genes.”

How and when genes are activated (or inactivated) can have a profound impact on human development, cancer and the biological legacy of environmental toxins. Prior to this research, PMDs had only been found in cultured cell lines, which led some scientists to wonder if they existed outside the test tube. This study confirms they exist in placental tissue, a critically important window into fetal development.

“The placenta is the interface between mother and fetus,” said LaSalle, who is a researcher affiliated with the UC Davis MIND Institute. “It’s a time capsule from when a lot of important methylation events occurred.”

In addition, placental tissue was interesting to study because it has a number of invasive characteristics often associated with cancer. In fact, a number of cancers, such as breast and colon, have widespread PMDs. LaSalle notes that anti-cancer epigenetic therapies that adjust methylation could be refined based on this improved understanding of PMDs.

This work could also enhance our ability to detect genetic defects. Methylation, and other epigenetic data, provides information that cannot be found in the genome alone. For example, the vast majority of cells in the body contain identical genetic code. However, the added information provided by methylation allows scientists to determine where specific DNA came from.

“Methylation patterns are like fingerprints, showing which tissue that DNA is derived from,” LaSalle said. “You can’t get that information from just the DNA sequence. As a result, methylation studies could be a very rich source for biomarkers.”

In the study, PMDs encompassed 37 percent of the placental genome, including 3,815 genes, around 17 percent of all genes. When found in low-methylation regions, these genes were less likely to be transcribed into proteins. Researchers also found that PMDs also contain more highly methylated CpG islands (genomic areas with large numbers of cytosine-guanine pairs), which are often associated with gene transcriptional silencing of promoters.

Because the placental PMDs contained many genes associated with neuronal development, and specifically autism, LaSalle notes that future research could investigate how epigenetics impacts autism genes at birth.

“We are looking for biomarkers that predict neurodevelopmental outcomes,” LaSalle said. “Now we have a series of snap shots from a critical period where we think environmental factors are playing a role in the developing brain.”

Why homosexuality occurs

Study finds epigenetics, not genetics, underlies homosexuality:

Study finds epigenetics, not genetics, underlies homosexuality

Study finds epigenetics, not genetics, underlies homosexuality

 

KNOXVILLE – Epigenetics – how gene expression is regulated by temporary switches, called epi-marks – appears to be a critical and overlooked factor contributing to the long-standing puzzle of why homosexuality occurs. According to the study, published online today in The Quarterly Review of Biology, sex-specific epi-marks, which normally do not pass between generations and are thus “erased,” can lead to homosexuality when they escape erasure and are transmitted from father to daughter or mother to son. From an evolutionary standpoint, homosexuality is a trait that would not be expected to develop and persist in the face of Darwinian natural selection. Homosexuality is nevertheless common for men and women in most cultures. Previous studies have shown that homosexuality runs in families, leading most researchers to presume a genetic underpinning of sexual preference. However, no major gene for homosexuality has been found despite numerous studies searching for a genetic connection. In the current study, researchers from the Working Group on Intragenomic Conflict at the National Institute for Mathematical and Biological Synthesis (NIMBioS) integrated evolutionary theory with recent advances in the molecular regulation of gene expression and androgen-dependent sexual development to produce a biological and mathematical model that delineates the role of epigenetics in homosexuality. Epi-marks constitute an extra layer of information attached to our genes’ backbones that regulates their expression. While genes hold the instructions, epi-marks direct how those instructions are carried out – when, where and how much a gene is expressed during development. Epi-marks are usually produced anew each generation, but recent evidence demonstrates that they sometimes carryover between generations and thus can contribute to similarity among relatives, resembling the effect of shared genes. Sex-specific epi-marks produced in early fetal development protect each sex from the substantial natural variation in testosterone that occurs during later fetal development. Sex-specific epi-marks stop girl fetuses from being masculinized when they experience atypically high testosterone, and vice versa for boy fetuses. Different epi-marks protect different sex-specific traits from being masculinized or feminized – some affect the genitals, others sexual identity, and yet others affect sexual partner preference. However, when these epi-marks are transmitted across generations from fathers to daughters or mothers to sons, they may cause reversed effects, such as the feminization of some traits in sons, such as sexual preference, and similarly a partial masculinization of daughters. The study solves the evolutionary riddle of homosexuality, finding that “sexually antagonistic” epi-marks, which normally protect parents from natural variation in sex hormone levels during fetal development, sometimes carryover across generations and cause homosexuality in opposite-sex offspring. The mathematical modeling demonstrates that genes coding for these epi-marks can easily spread in the population because they always increase the fitness of the parent but only rarely escape erasure and reduce fitness in offspring.”Transmission of sexually antagonistic epi-marks between generations is the most plausible evolutionary mechanism of the phenomenon of human homosexuality,” said the study’s co-author Sergey Gavrilets, NIMBioS’ associate director for scientific activities and a professor at the University of Tennessee-Knoxville.

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The paper’s other authors are William Rice, a professor at the University of California, Santa Barbara, and Urban Friberg, a professor at Uppsala University in Sweden. The National Institute for Mathematical and Biological Synthesis (NIMBioS) brings together researchers from around the world to collaborate across disciplinary boundaries to investigate solutions to basic and applied problems in the life sciences. NIMBioS is sponsored by the National Science Foundation, the U.S. Department of Homeland Security, and the U.S. Department of Agriculture with additional support from The University of Tennessee, Knoxville. Homosexuality as a consequence of epigenetically canalized sexual development.