How germ line epigenetic regulators contribute to gene expression during genomic instability

Abstract

Genetically identical individuals can have strikingly different phenotypes due to differences in gene expression. One reason for this is because epigenetic regulators can modulate mitotically or meiotically heritable changes in gene expression without changing DNA sequences. One way epigenetic factors can affect gene expression is by mediating how tightly DNA is packaged in the nucleus. When the DNA is tightly packed, in a structure known as heterochromatin, it is inaccessible for transcription, whereas lightly packed DNA, euchromatin, is accessible for transcription. The most well understood epigenetic regulators involve chemical modification of DNA like methylation and post-translational modifications of histone proteins, but small noncoding RNAs now are being recognized as important epigenetic regulators. Small RNAs can initiate the formation of heterochromatin as well as regulate genes post-transcriptionally by preventing the translation of mRNA. Piwi-interacting RNAs (piRNAs) are maternally transmitted small RNAs that control mutagenic transposable elements (TEs). There is a striking interplay between heterochromatin formation and piRNA function as piRNAs target resident TE insertions for repression through heterochromatin formation. Although most DNA and chromatin based epigenetic marks are erased between generations, piRNA are directly deposited into the embryo to maintain TE repression across generations. Because piRNA can induce heterochromatin formation, the transgenerational transmission of piRNA is thought to be one of the ways that heterochromatin domains can be re-established in the embryo. In chapters one and two, I examine how disparate maternal piRNA pools influence gene expression using a sterility syndrome of hybrid dysgenesis in Drosophila virilis. Chapter 1 outlines the effects of TE silencing small RNAs on gene expression in the germline and subsequent effects on future generations. Chapter 2 extends that study to investigate how disparate piRNA profiles and gene silencing in the genome affect somatic gene expression. Misregulation of epigenetic regulators is associated with many diseases, ranging from kidney diseases and neurodegenerative diseases, to cancer. Recently, epigenetic regulation has been implicated as playing a key role in the aging process. In particular, the landscape of silent heterochromatin has been shown to redistribute in aged stem cells and cells of the soma, leading to aberrant gene and transposable element expression. Although important for understanding the biology of aging, these cells do not affect future generations. In fact, little is known about heritable epigenetic changes that occur in aged germline cells that do give rise to the next generation. In chapter 3, I investigate whether the epigenetic deregulation and TE derepression that has been shown to exist in the soma also exists in the Drosophila melanogaster germline.