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Lysine deacetylation and transcriptional dysregulation in neurological disorders: Huntington's disease and the Rubinstein-Taybi syndrome


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Lysine deacetylation and transcriptional dysregulation in neurological disorders: Huntington's disease and the Rubinstein-Taybi syndrome
Guiretti, Deisy Mariela
Barco Guerrero, Ángel
Valor Becerra, Luis Miguel
Instituto de Neurociencias
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Lysine deacetylation and transcriptional dysregulation in neurological disorders: Huntington¿s disease and the Rubinstein-Taybi syndrome Cognitive decline and other neurological symptoms associated with aging, neurodegenerative diseases such as Alzheimer¿s diseases or poliglutamines (polyQ) diseases (e.g. Huntington¿s disease (HD)) and congenital intellectual disability disorders (e.g., Rubinstein-Taybi syndrome (RSTS)) have been associated with reduced level of neuronal histone acetylation. Here we investigate the genome-wide correlation of histone acetylation and gene expression defects in a HD mouse model (HD82Q). Our analyses identified hundreds of loci that were hypoacetylated for H3K9/14 and H4K12 in the chromatin of HD82Q) mice. Surprisingly, few genes with altered transcript levels in mutant mice showed significant changes in these acetylation marks and vice versa. Genes in this group were consistently affected in different brain areas, mouse models and tissue from patients, which suggests a role in the etiology of this pathology. Overall, our histone acetylation and gene expression screens demonstrate that these phenomena are two early, largely independent, manifestations of polyQ disease. Subsequently, we extended the observation of the limited impact of polyQ pathology in global histone acetylation profiles to other animal and cellular HD models. In the absence of bulk chromatin changes, we documented histone deacetylation events at the transcription start sites (TSS) of relevant genes for neuronal functioning. These local deficits can be associated with an increased susceptibility for transcriptional dysregulation and defective trimethylation of histone H3 at lysine 4 (H3K4me3), another covalent modification of the histone tails related with active transcription that is also altered in HD. Overall, this study provides further insight into the nature and extent of epigenetic dysregulation in HD pathology. In the second part of this thesis we addressed the role of the CREB-binding protein (CBP), a transcriptional co-activator which mutation is linked to the RSTS. To this end, we generated and characterized a Nes-cre::CBPf/f mouse line. These mice presents the ablation of CBP in neural-derived cells, hence, they are usefull to determine the role of CBP in the development of the nervous system and the etiology of the RSTS). The absence of CBP in neural-derived cells caused perinatal death and severe neuronal growth defects in primary hippocampal cultures. Both phenotypes were associated with a severe histone hypoacetylation. In order to counteract the reduced histone acetylation observed in RSTS, we have designed and generated recombinant lentiviruses (LV) that overexpress the KAT activity of CBP specifically in neurons (KAT-LV). The KAT-LV vector efficiently reverted histone acetylation deficits and led to a partial recovery of the dendritic tree integrity in primary hippocampal cultures from homozygous embryos. This strategy may represent a novel therapeutic approach not only for RSTS but also for others neurological diseases associated with neuronal histone deacetylation like HD.
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CDU: Ciencias aplicadas: Medicina: Patología. Medicina clínica. Oncología: Neurología. Neuropatología. Sistema nervioso
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Tesis doctorales - Ciencias de la Salud

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