Unknown,Transcriptomics,Genomics,Proteomics

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Deficits in histone acetylation and methylation are restricted to specific loci in Huntington's disease models

ABSTRACT: The present study extends the analysis initiated in a previous report in the popular HD transgenic mouse strain N171-82Q (82Q) (Valor et al., 2013), to other diverse mHtt-expressing animal and cellular models. We show that bulk histone hypoacetylation is not a general rule. Moreover, examination of other histone post-traslational modifications led to a detailed study of the trimethylation of lysine 4 of histone H3 (H3K4me3), which is tightly associated with active genes (Lopez-Atalaya et al., 2013), by combining both single-gene and genome-wide approaches. Comparison of the 82Q and another animal model, the R6/1 strain, revealed that changes in the levels of bulk H3K4me3 may be correlated with the degree of methylation impairment for specific genes. Yet, these changes are restricted to few genomic positions. In any case, and reminiscent of the situation with histone acetylation (Valor et al., 2013; McFarland et al., 2012), deficits in histone H3 methylation do not follow a straight relationship with transcriptional dysregulation. Genome-wide profiling by high throughput sequencing of H3K4me3 in the adult hippocampus of N171-82Q (HD) and their wild-type littermates mice (WT). Chromatin immunoprecipitation (ChIP) was carried out using pooled whole hippocampal tissue from 3 mice. DNA libraries (HD, WT, input) were constructed and single-end sequenced (1x50bp) in HiSeq 2500 platform (Illumina).

ORGANISM(S): Mus musculus

SUBMITTER: jose lopez

PROVIDER: E-GEOD-63675 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Our aim was to find an effective treatment for the dysfunction in energy regulation and hypothalamic integrity occurring in many HuntingtonM-bM-^@M-^Ys disease (HD) patients and mouse models. HD is a neurodegenerative disease caused by an expanded CAG repeat and is characterized by mutant huntingtin aggregates, cell death, progressive motor impairment, and cognitive alterations. Changes in neuroendocrine function, body weight, energy metabolism, euglycemia, appetite function, sleep, and gut function can also occur. It is likely that the locus of these alterations is the hypothalamus. Male B6C3-Tg(HD82Gln)81Dbo/J (N171-82Q) mice and age-matched wild-type (WT) mice were used. Transgenic mice were identified by PCR analysis of tail DNA. N171-82Q mice express 82 polyglutamine repeats and display multiple HuntingtonM-bM-^@M-^Ys disease-like symptoms. Either Ex-4 (n=10, 300 M-BM-5L of 0.1 M-BM-5mol/L solution, Bachem, Torrance, CA), the GLP-1-transferrin hybrid molecule (n=10, GLP-1Tf, 1mg/kg), insulin (n=10, 5Units, Lantus) or a saline vehicle treatment (n=10, phosphate buffered saline, PBS; Sigma, St. Louis, MO) was administered by a once-daily subcutaneous injection. Injections were started when animals were pre-symptomatic (2 months of age) and continued for 5 weeks. 3 Mice from each treatment qroup were used for the microarray analysis. RNA was extracted from frozen hypothalamus tissue using 1.0mm glass beads (BioSpec Products, Inc.) in a Precellys 24 Tissue Homogenizer (Bertin Technologies) and Qiagen RNeasy Mini Kits according to manufacturer's specifications. Quality and quantity of the total RNA was checked with the Agilent 2100 bioanalyzer using RNA 6000 Nano chips. The standard Illumina protocol using Illumina TotalPrep RNA Amplification Kit (Ambion; Austin, TX, cat # IL1791) was used to biotin label the aRNA generated and then hybridized to Illumina's Sentrix MouseRef-8 v2 Expression BeadChips (Illumina, San Diego, CA). Arrays were scanned at a resolution of 0.8um using the Beadstation 500 X from Illumina.

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Deficits in histone acetylation and methylation are restricted to specific loci in Huntington's disease models

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