Resumen de Caracterització epigenètica dels elements Alu i el seu paper en la regulació transcripcional
Berta Martín Abad
Epigenetics refers to heritable changes in gene expression that occur without alteration in DNA sequence. DNA methylation plays a crucial role in the regulation of chromatin architecture and in the control of gene expression. Even though DNA methylation is found mostly in repetitive elements and widespread hypomethylation was the first DNA methylation abnormality detected in tumors, there is a strong bias in methylation studies as most of them are restricted to CpG islands hypermethylation. For that reason, advances in understanding the epigenetic mechanisms that regulate repetitive elements may contribute to elucidate their specific participation in biological processes. Demethylation of repeat elements occurs in aging and pathological processes, as cancer, and has been associated with gene reactivation and genomic instability. Alu elements are the most abundant retrotransposon in the human genome, with more than 1 million copies. Interestingly, Alu elements tend to accumulate in gene rich regions. Alu elements contain up to 33% of the total number of CpG sites in the genome and are highly methylated in most somatic tissues. Strikingly, a small fraction of Alus remains unmethylated in normal cells and this proportion is increased in cancer cells. We hypothesize that Alu elements embedded in active chromatin are likely to participate in multiple cell processes, including crucial functions in development and cell identity. The main objective of this thesis has been to identify Alu elements with an active chromatin state and to determine their role in gene expression regulation. We have identified a subset of Alu elements with different epigenetic patterns characteristic of active functional states. We have observed that Alu elements have specific epigenetic profiles associated with pathological (cancer) or physiological (cell type) states and that the epigenetic particularity of Alus unmethylated in normal tissue is conserved at evolutional level. Moreover, we have identified and characterized two promoter regions corresponding to GLDC and DIEXF genes that include Alu elements (ZALU3 and Aj2c1, respectively) with a dynamic epigenetic pattern during development and cancer. These Alus show epigenetic changes that are consistent with the transcriptional and proteomic profiles of these genes and define the boundaries of the regulatory region.
