A role for heterochromatin and repetitive elements in epigenetic inheritance

Abstract

[eng] Gene regulation mechanisms control the level of transcription of each gene into RNA and the combination of expressed genes determines cell identity. Gene regulation is maintained by epigenetic mechanisms including DNA methylation, histone modifications and non-coding RNAs. These same mechanisms are responsible for silencing of transposable elements and heterochromatin formation. Interestingly, epigenetic mechanisms can transmit the transcriptional state of a gene to the next generation. Epigenetic inheritance differs from conventional genetics: it does not follow the law of segregation and importantly, can transmit acquired traits. The advent of next generation sequencing (NGS) allows for gene expression quantification and epigenome profiling, opening the door to genome wide screenings of epigenetic factors and phenotypes linked to epigenetic inheritance. Here, I study the role of heterochromatin and transposable elements in epigenetic inheritance. In the first chapter I present how an IAP insertion in the Nocturnin gene triggers the birth of new piRNA cluster in mouse. We hypothesize that many piRNA producing loci have evolved from ERV insertions into germline expressed genes. Last, we identify NXF1 as a key factor in piRNA biogenesis of IAP-derived piRNA loci. In the second chapter I test whether the IAP insertion in Nocturnin, and therefore piRNAs produced from this gene in the male germline, affect expression of the gene in the embryo. I find that the piRNA-producing allele of Nocturnin is more highly expressed from the paternal that the maternal allele in early embryo. Thus, the IAP insertion in Nocturnin leads to transmission of an altered epigenetic expression state from parents to progeny, potentially via the production of piRNAs in the male germline. In the third chapter of this thesis I describe a model of intergenerational epigenetic inheritance in flies. My work describes genome wide changes in gene expression that are direct consequences of epigenetic inheritance and I identify chromatin factors related to the transmission and maintenance of the phenotype in the next generation. In the fourth chapter of my thesis I use worms exposed to high temperature to identify endogenous genes that are able to maintain memory of expression for many generations. Interestingly, I find that transposable elements that are upregulated by temperature and repressed by heterochromatin can transmit epigenetic information to the progeny. In the fifth chapter of this thesis I study heritable expression of acquired expression states after epigenetic information loss linked to impaired DNA replication. My work describes how the loss of repressive marks during impaired replication in embryos leads to heritable changes in gene expression of loci regulated by heterochromatin and polycomb means.

[cat] Els mecanismes de regulació gènica controlen el nivell de transcripció de cada gen I l’estabilitat dels ARNs produïts. El perfil d’expressió gènica determina la identitat d’una cèl·lula, permetent que es formin teixits diferenciats partint d’exactament el mateix ADN. L’epigenètica és el conjunt de factors que asseguren que es mantingui el patró d’expressió gènica durant les divisions cel·lulars i el temps, i inclouen mecanismes com la metilació de l’ADN i la cromatina. També són responsables del silenciament d’elements repetitius i exògens presents al genoma. En aquesta tesi estudio el rol de l’epigenètica en transmetre informació d’expressió gènica no lligada a la seqüència d’ADN a les següents generacions. En concret, em centro en el paper que juguen l’heterocromatina i els elements repetitius en mantenir i transmetre canvis d’expressió a les següents generacions.