Transcriptional and Histone Acetylation Changes Associated with CRE Elements Expose Key Factors Governing the Regulatory Circuit in the Early Stage of Huntington’s Disease Models

Author:

Arancibia-Opazo Sandra123ORCID,Contreras-Riquelme J. Sebastián4,Sánchez Mario1ORCID,Cisternas-Olmedo Marisol567,Vidal René L.5678ORCID,Martin Alberto J. M.39ORCID,Sáez Mauricio A.11011ORCID

Affiliation:

1. Chromatin, Epigenetic, and Neuroscience Laboratory, Centro de Genómica y Bioinformática, Facultad de Ciencias, Ingeniería y Tecnología, Universidad Mayor, Santiago 8580745, Chile

2. Programa de Doctorado en Genómica Integrativa, Vicerrectoría de Investigación, Universidad Mayor, Santiago 8580745, Chile

3. Laboratorio de Redes Biológicas, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Universidad San Sebastián, Santiago 8580704, Chile

4. Plant Genome Regulation Lab, Centro de Biotecnología Vegetal, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370186, Chile

5. Centro de Biología Integrativa, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile

6. Biomedical Neuroscience Institute, University of Chile, Santiago 8380455, Chile

7. Center for Geroscience, Brain Health, and Metabolism, Santiago 8380453, Chile

8. Escuela de Biotecnología, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile

9. Escuela de Ingeniería, Facultad de Ingeniería, Arquitectura y Diseño, Universidad San Sebastián, Santiago 7500000, Chile

10. Centro de Oncología de Precisión, Facultad de Medicina Universidad Mayor, Santiago 7560908, Chile

11. Laboratorio de Investigación en Salud de Precisión, Departamento de Procesos Diagnósticos y Evaluación, Facultad de Ciencias de la Salud, Universidad Católica de Temuco, Temuco 4813302, Chile

Abstract

Huntington’s disease (HD) is a disorder caused by an abnormal expansion of trinucleotide CAG repeats within the huntingtin (Htt) gene. Under normal conditions, the CREB Binding Protein interacts with CREB elements and acetylates Lysine 27 of Histone 3 to direct the expression of several genes. However, mutant Htt causes depletion of CBP, which in turn induces altered histone acetylation patterns and transcriptional deregulation. Here, we have studied a differential expression analysis and H3K27ac variation in 4- and 6-week-old R6/2 mice as a model of juvenile HD. The analysis of differential gene expression and acetylation levels were integrated into Gene Regulatory Networks revealing key regulators involved in the altered transcription cascade. Our results show changes in acetylation and gene expression levels that are related to impaired neuronal development, and key regulators clearly defined in 6-week-old mice are proposed to drive the downstream regulatory cascade in HD. Here, we describe the first approach to determine the relationship among epigenetic changes in the early stages of HD. We determined the existence of changes in pre-symptomatic stages of HD as a starting point for early onset indicators of the progression of this disease.

Funder

Beca de Doctorado Nacional

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference89 articles.

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