Mechanisms of epigenetic memory

Abstract

Although genetics has an essential role in defining the development, morphology, and physiology of an organism, epigenetic mechanisms have an essential role in modulating these properties by regulating gene expression. During development, epigenetic mechanisms establish stable gene expression patterns to ensure proper differentiation. Such mechanisms also allow organisms to adapt to environmental changes and previous experiences can impact the future responsiveness of an organism to a stimulus over long timescales and even over generations. Here, we discuss the concept of epigenetic memory, defined as the stable propagation of a change in gene expression or potential induced by developmental or environmental stimuli. We highlight three distinct paradigms of epigenetic memory that operate on different timescales.

Keywords: chromatin; epigenetics; inheritance; memory; methylation; nuclear pore complex.

Figure 1. Types of epigenetic memory

A. Cellular memory: During early development, tissue-specific transcription factors establish different transcriptional programs. These programs are maintained through mitotic cell division later in development through the action of epigenetic regulators such as the Trithorax, which catalyzes methylation of histone H3, lysine 4 to promote sustained expression, and Polycomb, which catalyzes methylation of histone H3, lysine 27 to promote stable repression. B. Transcriptional memory: Environmental changes induce changes in gene expression. Following such an experience, some genes remain poised for faster reactivation for several generations. Upon gene activation, genes can experience a more robust secondary transcriptional response. Nuclear pore proteins (Nups) and specific histone marks at the nuclear pore (yeast) or nucleoplasm (higher eukaryotes) are required to establish and inherit this poised state. C. Transgenerational Memory: The parental experiences can impact the behavior of the offspring. In this example, environmental stress reduces maternal LG-ABN, which reduces the stress-tolerance of pups into adulthood. Low LG-ABN alters the expression of stress regulators, leading to greater stress sensitivity. This altered gene expression requires changes in DNA methylation and histone acetylation and is inherited in future generations (F1 and F2).

Figure 2. Transcriptional Memory is conserved between organisms

A. Model for yeast INO1 transcriptional memory. Upon repression, INO1 remains associated with the nuclear pore complex in the population of cells for three to four generations. This interaction requires a cis-acting DNA element called the MRS and leads to an altered chromatin state involving the incorporation of H2A.Z and dimethylation of histone H3, lysine 4 by COMPASS (H3K4me2). These changes, and effector complexes such as Set3C are required to allow binding of poised, preinitiation RNA Polymerase II to the promoter. B. A conserved mechanism primes IFN-γ-induced genes for faster or stronger reactivation in HeLa cells. After exposure to IFN-γ, the nuclear pore protein Nup98 (homologous to yeast Nup100) binds to the promoters of genes with memory. This interaction occurs in the nucleoplasm, near PML bodies. Similar to the yeast INO1 gene, genes that exhibit IFN-γ memory maintain H3K4me2 and poised RNAPII on their promoters. These similarities suggest the possibility of recruiting similar chromatin effector complexes.