Predicting age from the transcriptome of human dermal fibroblasts.
Ontology highlight
ABSTRACT:
SUBMITTER: Fleischer JG
PROVIDER: S-EPMC6300908 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
Publications
Predicting age from the transcriptome of human dermal fibroblasts.
Fleischer Jason G JG Schulte Roberta R Tsai Hsiao H HH Tyagi Swati S Ibarra Arkaitz A Shokhirev Maxim N MN Huang Ling L Hetzer Martin W MW Navlakha Saket S
Genome biology 20181220 1
Biomarkers of aging can be used to assess the health of individuals and to study aging and age-related diseases. We generate a large dataset of genome-wide RNA-seq profiles of human dermal fibroblasts from 133 people aged 1 to 94 years old to test whether signatures of aging are encoded within the transcriptome. We develop an ensemble machine learning method that predicts age to a median error of 4 years, outperforming previous methods used to predict age. The ensemble was further validated by t ...[more]
Similar Datasets
Project description:There is a marked heterogeneity in human lifespan and health outcomes for people of the same chronological age. Thus, one fundamental challenge is to identify molecular and cellular biomarkers of aging that could predict lifespan and be useful in evaluating lifestyle changes and therapeutic strategies in the pursuit of healthy aging. Here, we developed a computational method to predict biological age from gene expression data in skin fibroblast cells using an ensemble of machine learning classifiers. We generated an extensive RNA-seq dataset of fibroblast cell lines derived from 133 healthy individuals whose ages range from 1 to 94 years, and 10 patients with Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease. On this dataset, our method predicted chronological age with a median error of 4 years, outperforming algorithms proposed by prior studies that predicted age from DNA methylation [4–8] and gene expression data [6,9] for fibroblasts. Importantly, our method consistently predicted higher ages for Progeria patients compared to age-matched controls, suggesting that our algorithm can identify accelerated aging in humans. These results show that the transcriptome of skin fibroblasts retains important age-related signatures. Our computational tool may also be applicable to predicting age from other genome-wide datasets.
2018-11-16 | GSE113957 | GEO
Project description:Predicting age from the transcriptome of human dermal fibroblasts
| PRJNA454681 | ENA
Project description:Fibrosis occurs when collagen deposition and fibroblast proliferation replace healthy tissue. Red light (RL) may improve skin fibrosis via photobiomodulation, the process by which photosensitive chromophores in cells absorb visible or near-infrared light and undergo photophysical reactions. Our previous research demonstrated that high fluence RL reduces fibroblast proliferation, collagen deposition, and migration. Despite the identification of several cellular mechanisms underpinning RL phototherapy, little is known about the transcriptional changes that lead to anti-fibrotic cellular responses. Herein, RNA sequencing was performed on human dermal fibroblasts treated with RL phototherapy. Pathway enrichment and transcription factor analysis revealed regulation of extracellular matrices, proliferation, and cellular responses to oxygen-containing compounds following RL phototherapy. Specifically, RL phototherapy increased the expression of MMP1, which codes for matrix metalloproteinase-1 (MMP-1) and is responsible for remodeling extracellular collagen. Differential regulation of MMP1 was confirmed with RT-qPCR and ELISA. Additionally, RL upregulated PRSS35, which has not been previously associated with skin activity, but has known anti-fibrotic functions. Our results suggest that RL may benefit patients by altering fibrotic gene expression.
| S-EPMC8017006 | biostudies-literature
Project description:Epigenetic modifications of cytosine residues in the DNA play a critical role for cellular differentiation and potentially also for aging. In mesenchymal stromal cells (MSC) from human bone marrow we have previously demonstrated age-associated methylation changes at specific CpG-sites of developmental genes. In continuation of this work, we have now isolated human dermal fibroblasts from young (<23 years) and elderly donors (>60 years) for comparison of their DNA methylation profiles using the Infinium HumanMethylation27 assay. In contrast to MSC, fibroblasts could not be induced towards adipogenic, osteogenic and chondrogenic lineage and this is reflected by highly significant differences between the two cell types: 766 CpG sites were hyper-methylated and 752 CpG sites were hypo-methylated in fibroblasts in comparison to MSC. Strikingly, global DNA methylation profiles of fibroblasts from the same dermal region clustered closely together indicating that fibroblasts maintain positional memory even after in vitro culture. 75 CpG sites were more than 15% differentially methylated in fibroblasts upon aging. Very high hyper-methylation was observed in the aged group within the INK4A/ARF/INK4b locus and this was validated by pyrosequencing. Age-associated DNA methylation changes were related in fibroblasts and MSC but they were often regulated in opposite directions between the two cell types. In contrast, long-term culture associated changes were very consistent in fibroblasts and MSC. Epigenetic modifications at specific CpG sites support the notion that aging represents a coordinated developmental mechanism that seems to be regulated in a cell type specific manner.
| S-EPMC3035656 | biostudies-literature
Project description:BackgroundVemurafenib (PLX4032) is one of the most frequently used treatments for late-stage melanoma patients with the BRAFV600E mutation; however, acquired resistance to the drug poses as a major challenge. It remains to be determined whether off-target effects of vemurafenib on normal stroma components could reshape the tumor microenvironment in a way that contributes to cancer progression and drug resistance.MethodsBy using temporally-resolved RNA- and ATAC-seq, we studied the early molecular changes induced by vemurafenib in human dermal fibroblast (HDF), a main stromal component in melanoma and other tumors with high prevalence of BRAFV600 mutations.ResultsTranscriptomics analyses revealed a stepwise up-regulation of proliferation signatures, together with a down-regulation of autophagy and proteolytic processes. The gene expression changes in HDF strongly correlated in an inverse way with those in BRAFV600E mutant malignant melanoma (MaMel) cell lines, consistent with the observation of a paradoxical effect of vemurafenib, leading to hyperphosphorylation of MEK1/2 and ERK1/2. The transcriptional changes in HDF were not strongly determined by alterations in chromatin accessibility; rather, an already permissive chromatin landscape seemed to facilitate the early accessibility to MAPK/ERK-regulated transcription factor binding sites. Combinatorial treatment with the MEK inhibitor trametinib did not preclude the paradoxical activation of MAPK/ERK signaling in HDF. When administered together, vemurafenib partially compensated for the reduction of cell viability and proliferation induced by trametinib. These paradoxical changes were restrained by using the third generation BRAF inhibitor PLX8394, a so-called paradox breaker compound. However, the advantageous effects on HDF during combination therapies were also lost.ConclusionsVemurafenib induces paradoxical changes in HDF, enabled by a permissive chromatin landscape. These changes might provide an advantage during combination therapies, by compensating for the toxicity induced in stromal cells by less specific MAPK/ERK inhibitors. Our results highlight the relevance of evaluating the effects of the drugs on non-transformed stromal components, carefully considering the implications of their administration either as mono- or combination therapies. Video Abstract.
| S-EPMC8686565 | biostudies-literature
Project description:Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%-80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%-20% killing) and adult fibroblasts (20 years old; ∼10%-30% killing). Old fibroblasts also displayed significantly increased (2-4-fold) steady-state levels of O2•-, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•- in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•- and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054-67. ©2017 AACR.
| S-EPMC5600863 | biostudies-literature
Project description:The recognition of a distinct fat depot, the dermal white adipose tissue (dWAT), points out the complexity of the interaction among skin resident cells: keratinocytes, dermal fibroblasts (DFs) and adipocytes in response to physiological (diet, age) and pathological (injury) stimulations. dWAT has been recognized as a significant contributor to thermoregulation, hair cycle, immune response, wound healing and scarring. In this study, we examined age- and diet-related changes in dWAT modulation and DFs' adipogenic potential. The data showed that diet modulates dWAT expansion predominantly by hypertrophy, whereas age affects the pool of adipocyte progenitor cells in the skin indicating its role in dWAT hyperplasia. Analysis of DFs' migratory abilities in the model of skin explants isolated from the skin of young, old, low (LFD)- or high (HFD)-fat diet C56BL/6 mice revealed that HFD, regardless of animal age has the most profound stimulatory impact of DF migration. We determined that the adipogenic potential of DFs is comparable to stromal vascular fraction (SVF) of inguinal fat depot and ear mesenchymal stem cells (EMSC). We also showed the stimulatory role of epidermally expressed transcription factor Foxn1 on adipogenic signaling: bone morphogenetic protein 2 (Bmp2) and insulin-like growth factor 2 (Igf2) in keratinocytes.
| S-EPMC7728337 | biostudies-literature
Project description:BackgroundBy comparing fibroblasts collected from animals at 5-months or 16-months of age we have previously found that the cultures from older animals produce much more IL-8 in response to lipopolysaccharide (LPS) stimulation. We now expand this finding by examining whole transcriptome differences in the LPS response between cultures from the same animals at different ages, and also investigate the contribution of DNA methylation to the epigenetic basis for the age-dependent increases in responsiveness.ResultsAge-dependent differences in IL-8 production by fibroblasts in response to LPS exposure for 24 h were abolished by pretreatment of cultures with a DNA demethylation agent, 5-aza-2'deoxycytidine (AZA). RNA-Seq analysis of fibroblasts collected from the same individuals at either 5 or 16 months of age and exposed in parallel to LPS for 0, 2, and 8 h revealed a robust response to LPS that was much greater in the cultures from older animals. Pro-inflammatory genes including IL-8, IL-6, TNF-α, and CCL20 (among many other immune associated genes), were more highly expressed (FDR < 0.05) in the 16-month old cultures following LPS exposure. Methylated CpG island recovery assay sequencing (MIRA-Seq) revealed numerous methylation peaks spread across the genome, combined with an overall hypomethylation of gene promoter regions, and a remarkable similarity, except for 20 regions along the genome, between the fibroblasts collected at the two ages from the same animals.ConclusionsThe fibroblast pro-inflammatory response to LPS increases dramatically from 5 to 16 months of age within individual animals. A better understanding of the mechanisms underlying this process could illuminate the physiological processes by which the innate immune response develops and possibly individual variation in innate immune response arises. In addition, although relatively unchanged by age, our data presents a general overview of the bovine fibroblast methylome as a guide for future studies in cattle epigenetics utilizing this cell type.
| S-EPMC4312471 | biostudies-literature
Project description:Stromal cells have been widely used in biomedical research and disease modeling studies in vitro. The most commonly used types of stromal cells are mesenchymal stem cells and fibroblasts. Their cellular phenotypes and differentiation capabilities are quite similar and there are no specific distinction criteria. In order to identify transcriptomic differences between these 2 cell types, we performed next-generation RNA sequencing. Using the global gene expression profile and pathway analysis, we showed that human primary bone marrow mesenchymal stem cells and human primary dermal fibroblasts have different molecular signatures. We also identified critical transcription factors that are differentially expressed between these cells. We then proposed that homeobox genes and some other sequence-specific transcription factors are not only responsible for transcriptional differences, but also discriminate bone marrow mesenchymal stem cells and dermal fibroblasts at the transcriptional level.
| S-EPMC6426640 | biostudies-literature
Project description:Brown adipogenesis contributes to controlling systemic energy balance by enhancing glucose and lipid consumptions. We have previously reported chemical compound-induced brown adipocytes (ciBAs) directly converted from human dermal fibroblasts using a serum-free medium. In this study, genome-wide transcriptional analysis was performed in ciBAs in comparison with the control fibroblasts. A broad range of integrated gene expression was enhanced in functional groups including tricarboxylic acid cycle, electron transfer chain, triglycerides metabolism, fatty acid and glucose metabolism, and adaptive thermogenesis. The results suggested that the chemical conversion underwent metabolic and mitochondrial reprogramming closely associated with functions in brown/beige adipocytes. Moreover, we also compared the transcriptional changes to those of adipocyte browning in adipose tissue-derived mesenchymal stem cells (AdMSCs). Transcriptome analysis indicated that the same sets of metabolic and mitochondria-related genes were similarly changed in the adipocyte browning. Interestingly, ciBAs more expressed Ucp1, while AdMSC-derived adipocytes predominantly expressed Ucp2. UCP1 protein was also more expressed in ciBAs than in AdMSC-derived adipocytes. Based on the evidence that UCP1, but not UCP2, is responsible for adrenergic thermogenesis, ciBAs could be a promising model for human beige adipocytes applicable for basic research, drug development, and clinical uses.
| S-EPMC7930091 | biostudies-literature