scholarly journals Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses

2018 ◽  
Author(s):  
Bérénice A. Benayoun ◽  
Elizabeth A. Pollina ◽  
Param Priya Singh ◽  
Salah Mahmoudi ◽  
Itamar Harel ◽  
...  
Keyword(s):  
Gene Expression Regulation ◽  
Inflammatory Responses ◽  
Functional Decline ◽  
Histone H3 ◽  
Interferon Response ◽  
System Response ◽  
Age Related ◽  
Transcriptional Changes ◽  
Transcriptomic Changes ◽  
H3 Acetylation

AbstractAging is accompanied by the functional decline of tissues. However, a systematic study of epigenomic and transcriptomic changes across tissues during aging is missing. Here we generated chromatin maps and transcriptomes from 4 tissues and one cell type from young, middle-age, and old mice, yielding 143 high-quality datasets. We focused specifically on chromatin marks linked to gene expression regulation and cell identity: histone H3 trimethylation at lysine 4 (H3K4me3), a mark enriched at promoters, and histone H3 acetylation at lysine 27 (H3K27ac), a mark enriched at active enhancers. Epigenomic and transcriptomic landscapes could easily distinguish between ages, and machine learning analysis showed that specific epigenomic states could predict transcriptional changes during aging. Analysis of datasets from all tissues identified recurrent age-related chromatin and transcriptional changes in key processes, including the upregulation of immune system response pathways such as the interferon signaling pathway. The upregulation of interferon response pathway with age was accompanied by increased transcription of various endogenous retroviral sequences. Pathways deregulated during mouse aging across tissues, notably innate immune pathways, were also deregulated with aging in other vertebrate species – African turquoise killifish, rat, and humans – indicating common signatures of age across species. To date, our dataset represents the largest multi-tissue epigenomic and transcriptomic dataset for vertebrate aging. This resource identifies chromatin and transcriptional states that are characteristic of youthful tissues, which could be leveraged to restore aspects of youthful functionality to old tissues.

scholarly journals The aging skin microenvironment dictates stem cell behavior

2020 ◽  
Vol 117 (10) ◽  
pp. 5339-5350 ◽  
Author(s):  
Yejing Ge ◽  
Yuxuan Miao ◽  
Shiri Gur-Cohen ◽  
Nicholas Gomez ◽  
Hanseul Yang ◽  
...  
Keyword(s):  
Dominant Role ◽  
Functional Decline ◽  
Cell Types ◽  
Multiple Organs ◽  
Age Related ◽  
Hair Follicle Stem Cells ◽  
Aged Skin ◽  
Transcriptional Changes ◽  
Follicle Stem Cells

Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.

scholarly journals Transcriptional Changes in CD16+ Monocytes May Contribute to the Pathogenesis of COVID-19

2021 ◽  
Vol 12 ◽  
Author(s):  
Vanessa Chilunda ◽  
Pablo Martinez-Aguado ◽  
Li C. Xia ◽  
Laura Cheney ◽  
Aniella Murphy ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Cell Activation ◽  
Viral Infections ◽  
Inflammatory Responses ◽  
Interferon Response ◽  
Healthy Individuals ◽  
Sequencing Data ◽  
Transcriptional Changes ◽  
Severity Of The Disease

The COVID-19 pandemic has caused more than three million deaths globally. The severity of the disease is characterized, in part, by a dysregulated immune response. CD16+ monocytes are innate immune cells involved in inflammatory responses to viral infections, and tissue repair, among other functions. We characterized the transcriptional changes in CD16+ monocytes from PBMC of people with COVID-19, and from healthy individuals using publicly available single cell RNA sequencing data. CD16+ monocytes from people with COVID-19 compared to those from healthy individuals expressed transcriptional changes indicative of increased cell activation, and induction of a migratory phenotype. We also analyzed COVID-19 cases based on severity of the disease and found that mild cases were characterized by upregulation of interferon response and MHC class II related genes, whereas the severe cases had dysregulated expression of mitochondrial and antigen presentation genes, and upregulated inflammatory, cell movement, and apoptotic gene signatures. These results suggest that CD16+ monocytes in people with COVID-19 contribute to a dysregulated host response characterized by decreased antigen presentation, and an elevated inflammatory response with increased monocytic infiltration into tissues. Our results show that there are transcriptomic changes in CD16+ monocytes that may impact the functions of these cells, contributing to the pathogenesis and severity of COVID-19.

scholarly journals Spontaneous Eye Blinks Predict Executive Functioning in Seniors

2021 ◽  
Author(s):  
Jessika I. V. Buitenweg ◽  
Jaap M. J. Murre ◽  
K. Richard Ridderinkhof
Keyword(s):  
Older Adults ◽  
Working Memory ◽  
Executive Functioning ◽  
Cognitive Training ◽  
Functional Decline ◽  
Future Research ◽  
Blink Rate ◽  
Memory Updating ◽  
Age Related ◽  
Working Memory Updating

AbstractAs the world’s population is aging rapidly, cognitive training is an extensively used approach to attempt improvement of age-related cognitive functioning. With increasing numbers of older adults required to remain in the workforce, it is important to be able to reliably predict future functional decline, as well as the individual advantages of cognitive training. Given the correlation between age-related decline and striatal dopaminergic function, we investigated whether eye blink rate (EBR), a non-invasive, indirect indicator of dopaminergic activity, could predict executive functioning (response inhibition, switching and working memory updating) as well as trainability of executive functioning in older adults. EBR was collected before and after a cognitive flexibility training, cognitive training without flexibility, or a mock training. EBR predicted working memory updating performance on two measures of updating, as well as trainability of working memory updating, whereas performance and trainability in inhibition and switching tasks could not be predicted by EBR. Our findings tentatively indicate that EBR permits prediction of working memory performance in older adults. To fully interpret the relationship with executive functioning, we suggest future research should assess both EBR and dopamine receptor availability among seniors.

scholarly journals Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anastasiya Börsch ◽  
Daniel J. Ham ◽  
Nitish Mittal ◽  
Lionel A. Tintignac ◽  
Eugenia Migliavacca ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Inflammatory Responses ◽  
Molecular Data ◽  
Model Organisms ◽  
Sequencing Data ◽  
Phenotypic Analysis ◽  
Age Related ◽  
Analogous Data ◽  
Species Specific ◽  
And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

scholarly journals Dendranthema zawadskii var. lucidum (Nakai) J.H. Park Extract Inhibits Cellular Senescence in Human Dermal Fibroblasts and Aging-Related Inflammation in Rats

Processes ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 801
Author(s):  
Jehun Choi ◽  
Gwi-Yeong Jang ◽  
Jeonghoon Lee ◽  
Hae-Young Chung ◽  
Hyung-Jun Noh ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Cell Cycle Progression ◽  
Inflammatory Responses ◽  
Dermal Fibroblast ◽  
Dermal Fibroblasts ◽  
Dependent Manner ◽  
Aged Rats ◽  
Age Related ◽  
Dendranthema Zawadskii ◽  
Beta Galactosidase

Senescence is the phenomenon by which physiological functions of organisms degenerate with time. Cellular senescence is marked by an inhibition of cell cycle progression. Beta-galactosidase accumulates in the lysosomes of aged cells. In this study, human dermal fibroblast cells (HDFs) were treated with 0.5 μM doxorubicin for 4 h to induce cellular senescence. Senescence-associated beta-galactosidase (SA-β-gal) activity was then measured 72 h after treatment with aerial parts of Dendranthema zawadskii var. lucidum (Nakai) J.H. Park (DZ) extract. Treatment with DZ extract significantly decreased SA-β-gal activity in a dose-dependent manner in HDFs. Additionally, DZ extract treatment reduced age-related oxidative stress and inflammation in the aortas of aged rats. The reactive oxygen species (ROS) levels in aortas of aged control rats were higher than those in young rats. However, DZ extract-fed aged rats showed significantly lower ROS levels than the aged control rats. When the aged rats were treated with DZ extract at either 0.2 or 1.0 mg∙kg−1∙day−1, NF-κB levels in aorta tissue decreased significantly compared to those in aorta tissue of the aged control rats without DZ treatment. In addition, DZ extract-fed aged rat aortas showed significant reductions in expression of iNOS and COX-2 induced by NF-κB translocation. Therefore, these results suggest that DZ effectively inhibited senescence-related NF-κB activation and inflammation. DZ extract may have a role in the prevention of the vascular inflammatory responses that occur during vascular aging.

scholarly journals Random errors in protein synthesis activate an age-dependent program of muscle atrophy in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
James Moore ◽  
Rashid Akbergenov ◽  
Martina Nigri ◽  
Patricia Isnard-Petit ◽  
Amandine Grimm ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Atrophy ◽  
Strength Analysis ◽  
Dependent Manner ◽  
Random Errors ◽  
Age Related ◽  
Related Phenotype ◽  
Age Dependent ◽  
Translation Accuracy ◽  
Transcriptomic Changes

AbstractRandom errors in protein synthesis are prevalent and ubiquitous, yet their effect on organismal health has remained enigmatic for over five decades. Here, we studied whether mice carrying the ribosomal ambiguity (ram) mutation Rps2-A226Y, recently shown to increase the inborn error rate of mammalian translation, if at all viable, present any specific, possibly aging-related, phenotype. We introduced Rps2-A226Y using a Cre/loxP strategy. Resulting transgenic mice were mosaic and showed a muscle-related phenotype with reduced grip strength. Analysis of gene expression in skeletal muscle using RNA-Seq revealed transcriptomic changes occurring in an age-dependent manner, involving an interplay of PGC1α, FOXO3, mTOR, and glucocorticoids as key signaling pathways, and finally resulting in activation of a muscle atrophy program. Our results highlight the relevance of translation accuracy, and show how disturbances thereof may contribute to age-related pathologies.

scholarly journals The chromatin-binding protein HMGN3 stimulates histone acetylation and transcription across the Glyt1 gene

2012 ◽  
Vol 442 (3) ◽  
pp. 495-505 ◽  
Author(s):  
Gráinne Barkess ◽  
Yuri Postnikov ◽  
Chrisanne D. Campos ◽  
Shivam Mishra ◽  
Gokula Mohan ◽  
...  
Keyword(s):  
Histone Modifications ◽  
Splice Variants ◽  
Binding Protein ◽  
Histone H3 ◽  
Camp Response Element Binding ◽  
Element Binding Protein ◽  
H3k14 Acetylation ◽  
H3 Acetylation

HMGNs are nucleosome-binding proteins that alter the pattern of histone modifications and modulate the binding of linker histones to chromatin. The HMGN3 family member exists as two splice forms, HMGN3a which is full-length and HMGN3b which lacks the C-terminal RD (regulatory domain). In the present study, we have used the Glyt1 (glycine transporter 1) gene as a model system to investigate where HMGN proteins are bound across the locus in vivo, and to study how the two HMGN3 splice variants affect histone modifications and gene expression. We demonstrate that HMGN1, HMGN2, HMGN3a and HMGN3b are bound across the Glyt1 gene locus and surrounding regions, and are not enriched more highly at the promoter or putative enhancer. We conclude that the peaks of H3K4me3 (trimethylated Lys4 of histone H3) and H3K9ac (acetylated Lys9 of histone H3) at the active Glyt1a promoter do not play a major role in recruiting HMGN proteins. HMGN3a/b binding leads to increased H3K14 (Lys14 of histone H3) acetylation and stimulates Glyt1a expression, but does not alter the levels of H3K4me3 or H3K9ac enrichment. Acetylation assays show that HMGN3a stimulates the ability of PCAF [p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor] to acetylate nucleosomal H3 in vitro, whereas HMGN3b does not. We propose a model where HMGN3a/b-stimulated H3K14 acetylation across the bodies of large genes such as Glyt1 can lead to more efficient transcription elongation and increased mRNA production.

scholarly journals Role of CxxC-finger protein 1 in establishing mouse oocyte epigenetic landscapes

2021 ◽  
Author(s):  
Qian-Qian Sha ◽  
Ye-Zhang Zhu ◽  
Yunlong Xiang ◽  
Jia-Li Yu ◽  
Xiao-Ying Fan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone H3 ◽  
Finger Protein ◽  
Maternal Genome ◽  
Wide Range ◽  
Transcriptional Changes ◽  
Nuclear Events ◽  
Genomic Regions ◽  
Cxxc Finger Protein 1

Abstract During oogenesis, oocytes gain competence and subsequently undergo meiotic maturation and prepare for embryonic development; trimethylated histone H3 on lysine-4 (H3K4me3) mediates a wide range of nuclear events during these processes. Oocyte-specific knockout of CxxC-finger protein 1 (CXXC1, also known as CFP1) impairs H3K4me3 accumulation and causes changes in chromatin configurations. This study investigated the changes in genomic H3K4me3 landscapes in oocytes with Cxxc1 knockout and the effects on other epigenetic factors such as the DNA methylation, H3K27me3, H2AK119ub1 and H3K36me3. H3K4me3 is overall decreased after knocking out Cxxc1, including both the promoter region and the gene body. CXXC1 and MLL2, which is another histone H3 methyltransferase, have nonoverlapping roles in mediating H3K4 trimethylation during oogenesis. Cxxc1 deletion caused a decrease in DNA methylation levels and affected H3K27me3 and H2AK119ub1 distributions, particularly at regions with high DNA methylation levels. The changes in epigenetic networks implicated by Cxxc1 deletion were correlated with the transcriptional changes in genes in the corresponding genomic regions. This study elucidates the epigenetic changes underlying the phenotypes and molecular defects in oocytes with deleted Cxxc1 and highlights the role of CXXC1 in orchestrating multiple factors that are involved in establishing the appropriate epigenetic states of maternal genome.

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