Unravelling the epigenomic, transcriptomic and cognitive interplay in down syndrome
- Autores: Cèsar Lluís Sierra Noguera
- Directores de la Tesis: Mara Dierssen Sotos (dir. tes.)
- Lectura: En la Universitat Pompeu Fabra ( España ) en 2022
- Idioma: inglés
- Tribunal Calificador de la Tesis: Ana Pombo (presid.), Andrés Ozaita Mintegui (secret.), Timothy Bredy (voc.)
- Programa de doctorado: Programa de Doctorado en Biomedicina por la Universidad Pompeu Fabra
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
The presence of an extra copy of Human Chromosome 21 (HSA21) in Down syndrome (DS) is one of the most complex genetic perturbations compatible with life and is the most common genetic cause of intellectual disability. Even though great advances in the last decades have allowed better delineation of its pathogenetic mechanisms, its cellular and molecular bases remain poorly understood. Most research has focused on studying the gene dosage effects resulting from the triplication of specific HSA21 genes. However, the supernumerary HSA21 results not only in an increase of transcript levels of resident genes, but also in altered expression of a high number of non-HSA21 genes. This is probably due to the impact of the overexpression of HSA21 transcription factors, chromatin modifying enzymes and non-coding RNAs (ncRNAs) on the gene expression regulatory landscape. However, the study of the particular mechanisms involved in this perturbation has been addressed in bulk transcriptomic experiments from mixed cell populations, an approach largely limited by the fact that these mechanisms are highly cell-type specific.
To overcome this limitation, we performed the first comprehensive assessment of the cell-specific molecular changes that occur in the hippocampus of a mouse model of DS, Ts65Dn, by characterizing the transcriptome of tens of thousands of individual hippocampal neurons in parallel. This analysis revealed that the perturbations caused by the trisomy on the transcriptome are highly dependent on cellular identity, and led to the identification of genes, processes and cell composition alterations possibly involved in the DS pathogenetic mechanisms that were previously missed in bulk studies. Among them, we have unveiled the involvement of the long non-coding RNA gene Snhg11, specifically downregulated in the trisomic dentate gyrus, in adult neurogenesis and hippocampal-dependent cognitive phenotypes.
We also identified a disruption of chromatin state that could contribute to the observed genome-wide transcriptional alterations and interfere with the patterns of gene expression required for memory formation. In particular, we found a marked decrease of the global histone acetylation levels in the trisomic hippocampus accompanied by a decrease of chromatin accessibility at gene promoters. Importantly, administering trisomic mice with a histone deacetylase inhibitor (HDACi) rescued histone hypoacetylation and restored expression of the memory-related Arc gene upon learning. In line with these results, the administration of HDACi also led to a total recovery of long-term recognition memory in trisomic mice. Altogether, our results provide evidence for a cell-specific perturbation of the transcriptome as a major contributor to hippocampus-dependent memory deficits in DS and for epigenetic deregulation as the source of such transcriptional alterations.
