New research from Oregon Health & Science University has provided significant insight into the reasons why early-onset puberty occurs in females. The research, which was conducted at OHSU’s Oregon National Primate Research Center, is published in the current early online edition of the journal Nature Neuroscience.
The paper explains how OHSU scientists are investigating the role of epigenetics in the control of puberty. Epigenetics refers to changes in gene activity linked to external factors that do not involve changes to the genetic code itself. The OHSU scientists believe improved understanding of these complex protein/gene interactions will lead to greater understanding of both early-onset (precocious) puberty and delayed puberty, and highlight new therapy avenues.
To conduct this research, scientists studied female rats, which like their human counterparts, go through puberty as part of their early aging process. These studies revealed that a group of proteins, called PcG proteins, regulate the activity of a gene called the Kiss1 gene, which is required for puberty to occur. When these PcG proteins diminish, Kiss1 is activated and puberty begins.
PcG proteins are produced by another set of genes that act as a biological switch during the embryonic stage of life. The role of these proteins is to turn off specific downstream genes at key developmental stages.
OHSU scientists found that both the activity of these “master” genes and their ability to turn off puberty are impacted by two forms of epigenetic control: a chemical modification of DNA known as DNA methylation, and changes in the composition of histones, a specialized set of proteins that modify gene activity by interacting with DNA.
Using this new information, researchers were then able to delay puberty in female rats. They accomplished this by increasing PcG protein levels in the hypothalamus of the brain using a targeted gene therapy approach so that Kiss1 activation failed to occur at the normal time in life. The hypothalamus is a region of the brain that controls reproductive development.
“While it was always understood that an organism’s genes determine the timing of puberty, the role of epigenetics in this process has never been recorded until now,” said Alejandro Lomniczi, Ph.D., a scientist in the Division of Neuroscience at the OHSU Oregon National Primate Research Center.
“Because epigenetic changes are driven by environmental, metabolic and cell-to-cell influences, these findings raise the possibility that a significant percentage of precocious and delayed puberty cases occurring in humans may be the result of environmental factors and other alterations in epigenetic control,” said Sergio Ojeda, D.V.M, who is also a scientist in the Division of Neuroscience at the OHSU ONPRC.
“There is also much more to be learned about the way that epigenetic factors may link environmental factors such as nutrition, man-made chemicals, social interactions and other day-today influences to the timing and completion of normal puberty.”
Collaborators in this research include:
Alberto Loche, Ph.D., a postdoctoral fellow currently at the Friedrich Miescher Institute for Biomedical Research Novartis Research Foundation, Basel, Switzerland
Juan Manuel Castellano, Ph.D., a postdoctoral fellow supported by a Marie Curie International Outgoing Fellowship within the 7th European Community Framework Programme
Hollis Wright, Ph.D., a postdoctoral fellow supported by an NIH Training grant in Reproductive Sciences
Gabi Kaidar, M.D., a postdoctoral fellow currently at Maccabi Health Services, Pardes-Hana, Israel
Oline Ronnekleiv, Ph.D., and Martha Bosh. M.S., at the Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Ore.
Gerd Pfeiffer, Ph.D., at the Division of Biology, Beckman Research Institute of the City of Hope, Duarte, Calif.
Gabriel Knoll, a graduate student currently at Department of Pediatrics, Oregon Health & Science University, Portland, Ore.
The U.S. National Science Foundation (Grant: IOS1121691) and National Institutes of Health (Grants: HD025123-ARRA and 8P51OD011092) funded this research.
The ONPRC is a registered research institution, inspected regularly by the United States Department of Agriculture. It operates in compliance with the Animal Welfare Act and has an assurance of regulatory compliance on file with the National Institutes of Health. The ONPRC also participates in the voluntary accreditation program overseen by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).
Oregon Health & Science University is a nationally prominent research university and Oregon’s only public academic health center. It serves patients throughout the region with a Level 1 trauma center and nationally recognized Doernbecher Children’s Hospital. OHSU operates dental, medical, nursing and pharmacy schools that rank high both in research funding and in meeting the university’s social mission. OHSU’s Knight Cancer Institute helped pioneer personalized medicine through a discovery that identified how to shut down cells that enable cancer to grow without harming healthy ones. OHSU Brain Institute scientists are nationally recognized for discoveries that have led to a better understanding of Alzheimer’s disease and new treatments for Parkinson’s disease, multiple sclerosis and stroke. OHSU’s Casey Eye Institute is a global leader in ophthalmic imaging, and in clinical trials related to eye disease.