Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation

Cheng, Hao; Xuan, Hongwen; Green, Christopher D.; Han, Yingbo; Sun, Na; Shen, Hongjie; McDermott, Joseph; Bennett, David A.; Lan, Fei; Han, Jing‐Dong J.

doi:10.1073/pnas.1800656115

Cited by 44 publications

(52 citation statements)

References 40 publications

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“…Transcriptome datasets of 591 pre-frontal cortex biopsies measured on several Affymetrix microarray platforms and via rnaSeq (Illumina HiSeq) were downloaded from NCBI GEO (Supplementary Table 1). These datasets originate from studies by Narayan et al [41], Barnes et al [4], Lu et al [36], Lanz et al [34], Chen et al [10], Hagenauer et al [24] and Cheng et al [11]. Table 1 shows the distribution of the datasets between female and male samples and over age groups.…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of human prefrontal cortex reveals activation of GFAP and decline of synaptic transmission in the aging brain

Wruck

Adjaye

2020

acta neuropathol commun

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Despite ongoing research efforts, mechanisms of brain aging are still enigmatic and need to be elucidated for a better understanding of age-associated cognitive decline. The aim of this study is to investigate aging in the prefrontal cortex region of human brain in a meta-analysis of transcriptome datasets. We analyzed 591 gene expression datasets pertaining to female and male human prefrontal cortex biopsies of distinct ages. We used hierarchical clustering and principal component analysis (PCA) to determine the influence of sex and age on global transcriptome levels. In sex-specific analysis we identified genes correlating with age and differentially expressed between groups of young, middle-aged and aged. Pathways and gene ontologies (GOs) over-represented in the resulting gene sets were calculated. Potential causal relationships between genes and between GOs were explored employing the Granger test of gene expression time series over the range of ages. The most outstanding results were the age-related decline of synaptic transmission and activated expression of glial fibrillary acidic protein (GFAP) in both sexes. We found an antagonistic relationship between calcium/calmodulin dependent protein kinase IV (CAMK4) and GFAP which may include regulatory mechanisms involving cAMP responsive element binding protein (CREB) and mitogen-activated protein kinase (MAPK, alias ERK). Common to both sexes was a decline in synaptic transmission, neurogenesis and an increased base-level of inflammatory and immune-related processes. Furthermore, we detected differences in dendritic spine morphogenesis, catecholamine signaling and cellular responses to external stimuli, particularly to metal (Zinc and cadmium) ions which were higher in female brains.

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Section: Discussionmentioning

confidence: 99%

Meta-analysis of human prefrontal cortex reveals activation of GFAP and decline of synaptic transmission in the aging brain

Wruck

Adjaye

2020

acta neuropathol commun

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“…The epigenetic alterations found during aging seem to depend on the residue modified within a histone and the position of the histone mark along the targeted gene or within the genome. For example, by RNA‐seq analysis, Cheng et al identified two sets of age‐regulated genes in PFC of both human and mouse: an age‐downregulated group mainly involved in neural function and an age‐upregulated group enriched in genes with inflammation‐related functions (Cheng et al, ). These results show that, whereas the levels of acetylated H3 lysine 27 (H3K27ac) were reduced with aging in the promoters of both groups of genes, significantly decreased H3K27ac levels were observed at the gene bodies of upregulated genes.…”

Section: Histone Post‐translational Modificationsmentioning

confidence: 99%

“…These results show that, whereas the levels of acetylated H3 lysine 27 (H3K27ac) were reduced with aging in the promoters of both groups of genes, significantly decreased H3K27ac levels were observed at the gene bodies of upregulated genes. These results suggest that broad gene‐body H3K27 acetylation would suppress rather than activate gene expression and that H3K27 deacetylation at gene bodies would lead to transcriptional activation of pro‐inflammatory genes (Cheng et al, ).…”

Section: Histone Post‐translational Modificationsmentioning

confidence: 99%

Epigenetic mechanisms related to cognitive decline during aging

Harman

Martín

2019

J of Neuroscience Research

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Cognitive decline is a hallmark of the aging nervous system, characterized by increasing memory loss and a deterioration of mental capacity, which in turn creates a favorable context for the development of neurodegenerative diseases. One of the most detrimental alterations that occur at the molecular level in the brain during aging is the modification of the epigenetic mechanisms that control gene expression. As a result of these epigenetic‐driven changes in the transcriptome most of the functions of the brain including synaptic plasticity, learning, and memory decline with aging. The epigenetic mechanisms altered during aging include DNA methylation, histone modifications, nucleosome remodeling, and microRNA‐mediated gene regulation. In this review, we examine the current evidence concerning the changes of epigenetic modifications together with the molecular mechanisms underlying impaired neuronal gene transcription during aging. Herein, we discuss the alterations of DNA methylation pattern that occur in old neurons. We will also describe the most prominent age‐related histone posttranslational modifications in the brain since changes in acetylation and methylation of specific lysine residues on H3 and H4 are associated to functional decline in the old. In addition, we discuss the role that changes in the levels of certain miRNAs would play in cognitive decline with aging. Finally, we provide an overview about the mechanisms either extrinsic or intrinsic that would trigger epigenetic changes in the aging brain, and the consequences of these changes, i.e., altered transcriptional profile and reactivation of transposable elements in old brain.

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“…Protein lysine acetylation (Kac) is a conserved posttranslational modification that links acetyl-coenzyme A metabolism, including histone and non-histone acetylation (Shakespear et al, 2011). Protein posttranslational acetylation and deacetylation processes are factors in many human diseases and vital development, including neurodegenerative diseases, nerve system development, pulmonary fibrosis, neuroprogenitor survival and proliferation, neuronal maturation, maturation of astrocytes inflammation, and immunity in vertebrates (Sun et al, 2013;Choudhary et al, 2014;Li et al, 2017;Cheng et al, 2018). Numerous studies proved that the immune response was different from organ to organ (Sun et al, 2014;Tapias and Wang, 2017).…”

Section: Introductionmentioning

confidence: 99%

Integrative Proteome and Acetylome Analyses of Murine Responses to Cryptococcus neoformans Infection

Sun

et al. 2020

Front. Microbiol.

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Cryptococcus neoformans is a causative agent for pulmonary infection and meningoencephalitis. Understanding the host's response to C. neoformans infection is critical for developing effective treatment. Even though some have elucidated the host response at the transcriptome level, little is known about how it modulates its defense machinery through the proteome mechanism or how protein posttranslational modification responds to the infection. In this work, we employed a murine infection model and mass spectrometry to systematically determine the proteome and acetylome statuses of lungs and brains in the early stage of infection. To extensively analyze the host response, we integrated the proteome data to the transcriptome results. Critical genes, including genes involved in phagosome, lysosome, and platelet activation are significantly altered in protein and gene expression during infection. In the acetylome analysis, we demonstrated that lung and brain tissues differentially regulate protein acetylation during infection. The three primary groups of proteins altered in acetylation status are histones, proteins involved in glucose and fatty acid metabolism, and proteins from the immune system. These analyses provide an integrative regulation network of the host responding to C. neoformans and shed new light on understanding the host's regulation mechanism when responding to C. neoformans.

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Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation

Cited by 44 publications

References 40 publications

Meta-analysis of human prefrontal cortex reveals activation of GFAP and decline of synaptic transmission in the aging brain

Meta-analysis of human prefrontal cortex reveals activation of GFAP and decline of synaptic transmission in the aging brain

Epigenetic mechanisms related to cognitive decline during aging

Integrative Proteome and Acetylome Analyses of Murine Responses to Cryptococcus neoformans Infection

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