Environmental Factor, June 2009, National Institute of Environmental Health Sciences
Guest Lecturer Offers New Insight into Heritable Epigenetic Changes
By Negin Martin
Christophe Herman, Ph.D., a professor in the Department of Molecular and Human Genetics at Baylor College of Medicine, gave the latest talk in the NIEHS Laboratory of Molecular Genetics (LMG) Fellows Invited Lecture Series on May 18. His presentation, titled "Beyond Mutation: Transcription and Protein Folding Errors Generate Heritable Epigenetic Change," was hosted by NIEHS Spontaneous Mutation and Repair Group Visiting Fellow Libertad Garcia Villada, Ph.D. (http://www.niehs.nih.gov/research/atniehs/labs/lmg/smdnar/staff.cfm)
Until recently, mutations in DNA sequences were considered to be the only form of heritable changes that defined phenotype. However, many cells with similar genes have different phenotypes. Epigenetic - "epi" meaning "over" or "above" in Greek - research such as Herman's bridges this gap in understanding heredity by investigating factors other than DNA mutations that effect phenotype.
Epigenetics is the study of heritable changes that alter gene expression without any changes to DNA sequence. DNA methylation, histone acetylation and small interfering RNAs are examples of heritable epigenetic gene regulation. Unlike DNA mutations, epigenetic changes are often reversible.
Herman (http://www.bcm.edu/genetics/facultyaz/herman.html) has studied a number of other physiological systems, including heat shock proteins, metalloproteases and transcriptional regulators, that can be involved in epigenetic alteration. His lecture at NIEHS was divided into two sections, illustrating examples of heritable gene regulation by bistable switches and their dysregulation by protein misfolding or transcription errors.
As Herman explained, genes do not manifest any phenotypes unless they are expressed. Bistable switches often regulate cell differentiation by turning genes on or off. To qualify as a switch, a protein needs to be poorly expressed and to be involved in a positive or double negative feed back loop. Abundant proteins are difficult to silence or modify.
Herman's group used the well-studied lac operon system in Escherichia coli bacteria to study epigenetic modifications by a poorly transcribed repressor. The lac repressor is transcribed once per cell generation, and its depletion turns the lacZYA gene on. The lacY gene product increases permeability to an inducer that keeps the gene on. In short, if the gene is on it resists being turned off by transporting its own inducer. By replacing the lacA gene with green fluorescent protein (GFP) in this bistable model, his team was able to monitor transient errors in transcription and determine their hereditability.
According to Herman, when RNA transcription is error prone due to polymerase infidelity or absence of quality control proteins such as GreA and GreB, epigenetic switching becomes more prevalent. Hence, using bacteria as a model organism, Herman showed that such errors in transcription are heritable.
Protein translation and misfolding also contribute to epigenetic changes. Herman pointed to immunity control of lambda as an example of an epigenetic switch by a protein that is poorly translated.
Throughout his talk, Herman called on analogies to clarify complicated concepts. In order to explain the importance of background in determining function, Herman used the physical state of agar. If agar is moved from a refrigerated environment where it is solid to a warmer temperature at 55°C, it retains its solid form. In contrast, if agar is boiled, it becomes liquid and remains liquid at 55°C. Therefore, the same substance exposed to two different backgrounds could illicit different physical properties at identical temperatures. This excellent analogy helped to explain the basic principle of epigenetics - that environmental background can dictate phenotype without altering DNA sequence.
As Herman's talk demonstrated, epigenetic mechanisms of inheritance are especially important in understanding cell response to the environment and toxins. Manipulating gene expression, rather than genetic sequence, may offer novel ways for reprogramming cell function and curing or preventing disease.
(Negin Martin, Ph.D., is a biologist in the NIEHS Laboratory of Neurobiology Viral Vector Core Facility and a 2009 Science Communication Fellow with Environmental Health Sciences. She recently completed a postdoctoral fellowship with the NIEHS Membrane Signaling Group.)