Age-associated chromatin relaxation is enhanced in Huntington’s disease mice

Park, Myungsun; Min, Byungkuk; Jeon, Kyuheum; Cho, Sunwha; Kim, Jisun; Jeon, Jeha; Song, Jinhoi; Kim, Seokho; Jeong, Sangkyun; Seo, Hyemyung; Kang, Yong‐Kook

doi:10.18632/aging.101193

Cited by 12 publications

(20 citation statements)

References 72 publications

(87 reference statements)

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“…In agreement with that, regions with gained chromatin accessibility in our ATAC-seq data showed decreased levels of lamin B1, correlative increased expression and were enriched in terms associated with cell division and development, more typically associated to glial than to neuronal cells 50 . While a previous study showed a general gain of chromatin accessibility in HD T-cells 51 , our hippocampal ATAC-seq data showed a bi-directionality in chromatin accessibility changes, with a clear compaction of neuronal-associated regulatory regions and increased chromatin relaxation in developmental related ones. This is in agreement with a recent study demonstrating that HD neuronal and glial cells are affected in opposite ways at transcriptional level 50 .…”

Section: Discussioncontrasting

confidence: 87%

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Alcalà-Vida

Garcia‐Forn

Creus-Muncunill

et al. 2020

Preprint

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Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing an involvement of increased lamin B1 levels in the pathophysiology of Huntington's disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging we demonstrate that nucleus from striatal medium-sized spiny and CA1 hippocampal neurons display increased lamin B1 levels, in correlation with altered nuclear morphology and nucleocytoplasmic transport disruption. Moreover, ChIP-sequencing analysis shows an alteration of lamin-associated chromatin domains in hippocampal nuclei, which could contribute to transcriptional alterations we determined by RNA sequencing. Supporting lamin B1 alterations as a causal role in mutant-huntingtin mediated neurodegeneration, pharmacological normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work point out increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.Keywords: chromatin accessibility, LAD, R6/1 mouse, nuclear morphology, nuclear permeability of the polyglutamine chain at the amino terminus of the huntingtin (Htt) protein inducing selfassociation and aggregation. Consequently, mutant Htt (mHtt) loses its biological functions and becomes toxic 13 . In HD, medium-sized spiny neurons (MSNs), the GABAergic output projection neurons that account for the vast majority (90-95%) of all striatal neurons, are mainly affected. Although motor symptoms are the most prominent, psychiatric alterations and cognitive decline appear first in HD patients, which become more evident as the disease progresses. Cognitive deficits are related to the dysfunction of the corticostriatal pathway and the hippocampus and, together with motor deficits, have been replicated in most HD mouse models 14 .Molecular mechanisms leading to nuclear lamina alterations in neurons expressing mHtt remain to be elucidated. Previous results from our lab suggested that decreased levels of the pro-apoptotic kinase PKC would lead to an aberrant accumulation of lamin B 15 which, in turn, could have a significant influence in the nuclear lamina structure 16,17 . Therefore, here we sought to deeply characterize the impact of lamin alterations in HD brain at physiological (studying nuclear lamina morphology and nucleo-cytoplasmic transport), transcriptomic (by generating RNA-sequencing (RNA-seq) data) and epigenetic (analyzing lamin chromatin binding and chromatin accessibility) levels by using the R6/1 transgenic mouse model of HD and human post-mortem brain samples. ResultsLamin B levels are increased in a region-specific manner in HD brain. Lamin B1, B2, and A/C protein levels were analyzed in the striatum, cortex and hippocampus of wild-type and R6/1 mice, a transgenic mouse model of HD over-expressing the exon 1 of the human mutant huntingtin 18 , at different ages. Western blot a...

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Section: Discussioncontrasting

confidence: 87%

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Alcalà-Vida

Garcia‐Forn

Creus-Muncunill

et al. 2020

Preprint

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“…Mice about 28 months of age, which correlates with humans ranging from 76 to 78 years of age, can be considered “very old” and generally show a 50% survivorship (The Jackson Laboratory; lifespan as a biomarker). For isolation of T cells, a spleen from each mouse was ground with frosted glass slides followed by a series of syringe homogenization as shrinking the needle sizes (from 18 to 27 gauges), and T cells were isolated by magnetic‐activated cell sorting (MACS; Pan T Cell Isolation Kit II, mouse; Miltenyi Biotec) as described elsewhere (Park et al, ). For skeletal muscles, the whole muscle tissues were completely frozen in liquid nitrogen, and they were ground to powder using a mortar and a pestle.…”

Section: Methodsmentioning

confidence: 99%

Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice

2019

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Changes in DNA methylation influence the aging process and contribute to aging phenotypes, but few studies have been conducted on DNA methylation changes in conjunction with skeletal muscle aging. We explored the DNA methylation changes in a variety of retroelement families throughout aging (at 2, 20, and 28 months of age) in murine skeletal muscles by methyl‐binding domain sequencing (MBD‐seq). The two following contrasting patterns were observed among the members of each repeat family in superaged mice: (a) hypermethylation in weakly methylated retroelement copies and (b) hypomethylation in copies with relatively stronger methylation levels, representing a pattern of “regression toward the mean” within a single retroelement family. Interestingly, these patterns depended on the sizes of the copies. While the majority of the elements showed a slight increase in methylation, the larger copies (>5 kb) displayed evident demethylation. All these changes were not observed in T cells. RNA sequencing revealed a global derepression of retroelements during the late phase of aging (between 20 and 28 months of age), which temporally coincided with retroelement demethylation. Following this methylation drift trend of “regression toward the mean,” aging tended to progressively lose the preexisting methylation differences and local patterns in the genomic regions that had been elaborately established during the early period of development.

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“…Of particular interest was whether the expression of those genes important for early development were affected in shNTs. We examined the expression of epi-driver genes, stemness genes, and genes associated with trophectoderm (TE) development (Min et al, 2015 ; Park et al, 2017 ). Figure 5A shows the heat-map of expression levels of epi-driver genes in bovine blastocysts.…”

Section: Resultsmentioning

confidence: 99%

Determination of Oocyte-Manipulation, Zygote-Manipulation, and Genome-Reprogramming Effects on the Transcriptomes of Bovine Blastocysts

Min

Kang

2018

Front. Genet.

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Somatic cell nuclear transfer (scNT) embryos suffer from damage caused by micro-operation (manipulation) and inefficient genome reprograming that hinder their normal development at different levels and in distinct ways. These two effects are inseparable in the nature of the scNT embryo, although methods to separately measure them are needed to improve scNT technology and evaluate incoming reprogramming tools. As an attempt to meet these demands, we made bovine sham nuclear-transfer (shNT) blastocysts, special embryos made with a standard nuclear-transfer procedure at the zygote stage, while retaining an intact genome. We compared their transcriptomes with those of other blastocysts derived by in-vitro fertilization (IVF) or scNT. Correlation analysis revealed a singularity of shNT blastocysts as they separately gathered from the others. Analysis of developmentally important genes revealed that, in shNTs, the stemness-associated differentially expressed genes (DEGs), including OCT4, were mostly underrepresented. Overrepresented epi-driver genes were largely associated with heterochromatin establishment and maintenance. By multilateral comparisons of their transcriptomes, we classified DEGs into three groups: 561 manipulation-associated DEGs (MADs) common to shNTs and scNTs, 764 donor genome-associated DEGs (DADs) specific to scNTs, and 1743 zygote manipulation-associated DEGs (zMADs) specific to shNTs. GO enrichment analysis generated various terms involving “cell-cell adhesion,” “translation,” and “transcription” for MADs and “cell differentiation” and “embryo implantation” for DADs. Because of the transcriptomic specificity of shNTs, we studied zMADs in detail. GO enrichment analysis with the 854 zMADs underrepresented in shNTs yielded terms related to protein and mitochondria homeostasis, while GO enrichment analysis of 889 shNT-high zMADs yielded terms related to endoplasmic reticulum stress and protein transport. We summarized the DEGs, which, with further investigation, may help improve our understanding of molecular events occurring in cloned embryos and our ability to control clonal reprogramming.

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Age-associated chromatin relaxation is enhanced in Huntington’s disease mice

Cited by 12 publications

References 72 publications

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice

Determination of Oocyte-Manipulation, Zygote-Manipulation, and Genome-Reprogramming Effects on the Transcriptomes of Bovine Blastocysts

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