scholarly journals A programmable fate decision landscape underlies single-cell aging in yeast

Science ◽  
2020 ◽  
Vol 369 (6501) ◽  
pp. 325-329 ◽  
Author(s):  
Yang Li ◽  
Yanfei Jiang ◽  
Julie Paxman ◽  
Richard O’Laughlin ◽  
Stephen Klepin ◽  
...  
Keyword(s):  
Single Cell ◽  
Quantitative Model ◽  
Genetically Engineered ◽  
Cellular Aging ◽  
Multiple Equilibrium ◽  
Cell Aging ◽  
Epigenetic Landscape ◽  
Replicative Aging ◽  
Different Types ◽  
Fate Decision

Chromatin instability and mitochondrial decline are conserved processes that contribute to cellular aging. Although both processes have been explored individually in the context of their distinct signaling pathways, the mechanism that determines which process dominates during aging of individual cells is unknown. We show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape of yeast replicative aging with multiple equilibrium states that represent different types of terminal states of aging. The structure of the landscape drives single-cell differentiation toward one of these states during aging, whereby the fate is determined quite early and is insensitive to intracellular noise. Guided by a quantitative model of the aging landscape, we genetically engineered a long-lived equilibrium state characterized by an extended life span.

scholarly journals An epigenetic landscape governs early fate decision in cellular aging

2019 ◽  
Author(s):  
Yang Li ◽  
Yanfei Jiang ◽  
Julie Paxman ◽  
Richard O’Laughlin ◽  
Lorraine Pillus ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Cell Fate ◽  
Quantitative Model ◽  
Cellular Aging ◽  
Multiple Equilibrium ◽  
Epigenetic Landscape ◽  
Genetically Engineer ◽  
Different Types ◽  
Extended Lifespan ◽  
Fate Decision

AbstractChromatin instability and mitochondrial decline are conserved processes that contribute to cellular aging. Although both processes have been explored individually in the context of their distinct signaling pathways, the mechanism that determines which cell fate arises in isogenic cells is unknown. Here, we show that interactions between the chromatin silencing and mitochondrial pathways lead to an epigenetic landscape with multiple equilibrium states that represent different types of terminal cellular states. Interestingly, the structure of the landscape drives single-cell differentiation towards one of these states during aging, whereby the fate is determined quite early and is insensitive to intracellular noise. Guided by a quantitative model of the aging landscape, we genetically engineer a new “long-lived” equilibrium state that is characterized by a dramatically extended lifespan.

scholarly journals WADDINGTON’S LANDSCAPE OF CELL AGING

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S208-S208
Author(s):  
Nan Hao ◽  
Yang Li ◽  
Yanfei Jiang ◽  
Julie Paxman ◽  
Richard O’Laughlin ◽  
...  
Keyword(s):  
Aging Process ◽  
Cellular Aging ◽  
Model Organisms ◽  
Cell Aging ◽  
Molecular Pathways ◽  
Network Nodes ◽  
Complex Process ◽  
Fate Decision ◽  
Multiple Network ◽  
And Function

Abstract Cellular aging is a complex process that involves many interwoven molecular processes. Studies in model organisms have identified many individual genes and factors that have profound effects on lifespan. However, how these genes and factors interact and function collectively to drive the aging process remains unclear. We investigated single-cell aging dynamics throughout the replicative lifespans of S. cerevisiae, and found that isogenic cells diverge towards two aging paths, with distinct phenotypic changes and death forms. We further identified specific molecular pathways driving each aging fate and revealed that these pathways interact and operate dynamically to enable an early-life switch that governs the aging fate decision and the progression towards death. Our work uncovers the interconnected molecular pathways that drives the aging process and opens up the possibility of designing interventions that simultaneously target multiple network nodes, instead of single genes, to more effectively extend the healthspan.

scholarly journals Identifying cell types from single-cell data based on similarities and dissimilarities between cells

2021 ◽  
Vol 22 (S3) ◽  
Author(s):  
Yuanyuan Li ◽  
Ping Luo ◽  
Yi Lu ◽  
Fang-Xiang Wu
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Spectral Clustering ◽  
Incidence Matrix ◽  
Expression Patterns ◽  
Cell Types ◽  
Clustering Method ◽  
Different Types ◽  
Cell Data ◽  
Spectral Clustering Method

Abstract Background With the development of the technology of single-cell sequence, revealing homogeneity and heterogeneity between cells has become a new area of computational systems biology research. However, the clustering of cell types becomes more complex with the mutual penetration between different types of cells and the instability of gene expression. One way of overcoming this problem is to group similar, related single cells together by the means of various clustering analysis methods. Although some methods such as spectral clustering can do well in the identification of cell types, they only consider the similarities between cells and ignore the influence of dissimilarities on clustering results. This methodology may limit the performance of most of the conventional clustering algorithms for the identification of clusters, it needs to develop special methods for high-dimensional sparse categorical data. Results Inspired by the phenomenon that same type cells have similar gene expression patterns, but different types of cells evoke dissimilar gene expression patterns, we improve the existing spectral clustering method for clustering single-cell data that is based on both similarities and dissimilarities between cells. The method first measures the similarity/dissimilarity among cells, then constructs the incidence matrix by fusing similarity matrix with dissimilarity matrix, and, finally, uses the eigenvalues of the incidence matrix to perform dimensionality reduction and employs the K-means algorithm in the low dimensional space to achieve clustering. The proposed improved spectral clustering method is compared with the conventional spectral clustering method in recognizing cell types on several real single-cell RNA-seq datasets. Conclusions In summary, we show that adding intercellular dissimilarity can effectively improve accuracy and achieve robustness and that improved spectral clustering method outperforms the traditional spectral clustering method in grouping cells.

scholarly journals FlsnRNA-seq: protoplasting-free full-length single-nucleus RNA profiling in plants

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yanping Long ◽  
Zhijian Liu ◽  
Jinbu Jia ◽  
Weipeng Mo ◽  
Liang Fang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cell Walls ◽  
Large Scale ◽  
Full Length ◽  
Cell Level ◽  
Root Cells ◽  
Rna Profiling ◽  
Different Types ◽  
Long Read ◽  
Single Nucleus

AbstractThe broad application of single-cell RNA profiling in plants has been hindered by the prerequisite of protoplasting that requires digesting the cell walls from different types of plant tissues. Here, we present a protoplasting-free approach, flsnRNA-seq, for large-scale full-length RNA profiling at a single-nucleus level in plants using isolated nuclei. Combined with 10x Genomics and Nanopore long-read sequencing, we validate the robustness of this approach in Arabidopsis root cells and the developing endosperm. Sequencing results demonstrate that it allows for uncovering alternative splicing and polyadenylation-related RNA isoform information at the single-cell level, which facilitates characterizing cell identities.

scholarly journals MBRS-46. CHARTING NEOPLASTIC AND IMMUNE CELL HETEROGENEITY IN HUMAN AND GEM MODELS OF MEDULLOBLASTOMA USING scRNAseq

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii406-iii406
Author(s):  
Andrew Donson ◽  
Kent Riemondy ◽  
Sujatha Venkataraman ◽  
Ahmed Gilani ◽  
Bridget Sanford ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Immune Cell ◽  
Genetically Engineered ◽  
Cellular Heterogeneity ◽  
Cell Heterogeneity ◽  
Transcriptomic Data ◽  
Single Cell Rna Sequencing ◽  
Transcript Profiles

Abstract We explored cellular heterogeneity in medulloblastoma using single-cell RNA sequencing (scRNAseq), immunohistochemistry and deconvolution of bulk transcriptomic data. Over 45,000 cells from 31 patients from all main subgroups of medulloblastoma (2 WNT, 10 SHH, 9 GP3, 11 GP4 and 1 GP3/4) were clustered using Harmony alignment to identify conserved subpopulations. Each subgroup contained subpopulations exhibiting mitotic, undifferentiated and neuronal differentiated transcript profiles, corroborating other recent medulloblastoma scRNAseq studies. The magnitude of our present study builds on the findings of existing studies, providing further characterization of conserved neoplastic subpopulations, including identification of a photoreceptor-differentiated subpopulation that was predominantly, but not exclusively, found in GP3 medulloblastoma. Deconvolution of MAGIC transcriptomic cohort data showed that neoplastic subpopulations are associated with major and minor subgroup subdivisions, for example, photoreceptor subpopulation cells are more abundant in GP3-alpha. In both GP3 and GP4, higher proportions of undifferentiated subpopulations is associated with shorter survival and conversely, differentiated subpopulation is associated with longer survival. This scRNAseq dataset also afforded unique insights into the immune landscape of medulloblastoma, and revealed an M2-polarized myeloid subpopulation that was restricted to SHH medulloblastoma. Additionally, we performed scRNAseq on 16,000 cells from genetically engineered mouse (GEM) models of GP3 and SHH medulloblastoma. These models showed a level of fidelity with corresponding human subgroup-specific neoplastic and immune subpopulations. Collectively, our findings advance our understanding of the neoplastic and immune landscape of the main medulloblastoma subgroups in both humans and GEM models.

scholarly journals Telomeres and replicative cellular aging of the human placenta and chorioamniotic membranes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tsung-Po Lai ◽  
Mark Simpson ◽  
Krunal Patel ◽  
Simon Verhulst ◽  
Jungsik Noh ◽  
...  
Keyword(s):  
Dna Damage ◽  
Preterm Birth ◽  
Telomere Length ◽  
Human Placenta ◽  
Replicative Senescence ◽  
Preterm Births ◽  
Full Term ◽  
Cellular Aging ◽  
Telomere Dysfunction ◽  
Replicative Aging

AbstractRecent hypotheses propose that the human placenta and chorioamniotic membranes (CAMs) experience telomere length (TL)-mediated senescence. These hypotheses are based on mean TL (mTL) measurements, but replicative senescence is triggered by short and dysfunctional telomeres, not mTL. We measured short telomeres by a vanguard method, the Telomere shortest length assay, and telomere-dysfunction-induced DNA damage foci (TIF) in placentas and CAMs between 18-week gestation and at full-term. Both the placenta and CAMs showed a buildup of short telomeres and TIFs, but not shortening of mTL from 18-weeks to full-term. In the placenta, TIFs correlated with short telomeres but not mTL. CAMs of preterm birth pregnancies with intra-amniotic infection showed shorter mTL and increased proportions of short telomeres. We conclude that the placenta and probably the CAMs undergo TL-mediated replicative aging. Further research is warranted whether TL-mediated replicative aging plays a role in all preterm births.

scholarly journals ATRT-13. DIFFERENT CELLS OF ORIGIN PAVE THE WAY FOR MOLECULAR HETEROGENEITY IN RHABDOID TUMORS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii278-iii278
Author(s):  
Monika Graf ◽  
Marta Interlandi ◽  
Natalia Moreno ◽  
Dörthe Holdhof ◽  
Viktoria Melcher ◽  
...  
Keyword(s):  
Single Cell ◽  
Expression Patterns ◽  
Time Frame ◽  
Precursor Cells ◽  
Genetically Engineered ◽  
Molecular Heterogeneity ◽  
Loss Of Function ◽  
Cellular Origin ◽  
Cells Of Origin ◽  
Rhabdoid Tumors

Abstract Rhabdoid tumors (RT) are rare but highly aggressive pediatric neoplasms. These tumors carry homozygous loss-of-function alterations of SMARCB1 in almost all cases with an otherwise low mutational load. RT arise at different intracranial (ATRT) as well as extracranial (MRT) anatomical sites. Three main molecular subgroups (ATRT-SHH, ATRT-TYR, ATRT-MYC) have been characterized for ATRT which are epigenetically and clinically diverse, while MRT show remarkable similarities with ATRT-MYC distinct from ATRT-SHH and ATRT-TYR. Even though there are hypotheses about various cells of origin among RT subgroups, precursor cells of RT have not yet been identified. Previous studies on the temporal control of SMARCB1 knockout in genetically engineered mouse models have unveiled a tight vulnerable time frame during embryogenesis with regard to the susceptibility of precursor cells to result in RT. In this study, we employed single-cell RNA sequencing to describe the intra- and intertumoral heterogeneity of murine ATRT-SHH and -MYC as well as extracranial MYC tumor cells. We defined subgroup-specific tumor markers for all RT classes but also observed a notable overlap of gene expression patterns in all MYC subgroups. By comparing these single-cell transcriptomes with available single-cell maps of early embryogenesis, we gained first insights into the cellular origin of RT. Finally, unsupervised clustering of published human RT methylation data and healthy control tissues confirmed the existence of different cells of origin for intracranial SHH tumors and MYC tumors independent of their anatomical localizations.

Evidence for novel aspects of Nox4 oxidase regulation of mitochondrial function and peroxide generation in an endothelial cell model of senescence

2013 ◽  
Vol 452 (2) ◽  
pp. e1-e2 ◽  
Author(s):  
Michael S. Wolin
Keyword(s):  
Endothelial Cell ◽  
Mitochondrial Function ◽  
Cell Model ◽  
Mitochondrial Fission ◽  
Cellular Aging ◽  
Cell Aging ◽  
Regulatory Processes ◽  
Napdh Oxidase ◽  
Transport Chain ◽  
Biochemical Journal

Observations by Kozieł et al. reported in this issue of the Biochemical Journal suggest the existence of novel regulatory processes associated with new evidence for increased Nox4 (NAPDH oxidase 4) regulation of mitochondrial function in a cultured endothelial cell aging-induced senescence model. Cellular aging appears to promote a Nox4 interaction with mitochondria that disrupts complex I in the electron transport chain and increases the detection of mitochondrial H2O2. Nox4 appears to maintain a highly interconnected mitochondrial network, which may influence mitochondrial fission and/or fusion mechanisms in a manner that could be a contributing factor in the loss of replicative lifespan seen in senescence.

scholarly journals ETMR-06. DISSECTING THE MOLECULAR AND DEVELOPMENTAL BASIS OF PINEOBLASTOMA THROUGH GENOMICS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii323-iii324
Author(s):  
Brian Gudenas ◽  
Bernhard Englinger ◽  
Anthony P Y Liu ◽  
Yiai Tong ◽  
David Meredith ◽  
...  
Keyword(s):  
Pineal Gland ◽  
Single Cell ◽  
Outcome Data ◽  
Genetically Engineered ◽  
Developmental Trajectory ◽  
Transcriptional Analysis ◽  
Molecular Heterogeneity ◽  
Developmental Origins ◽  
Cell Of Origin ◽  
Molecular Features

Abstract Pineoblastoma (PB) is an aggressive embryonal brain tumor comprising 1% of pediatric CNS tumors. The clinico-molecular heterogeneity and developmental origins underlying PB are poorly understood; therefore, we have assembled a molecular cohort of histologically defined PBs (n=43) with corresponding outcome data. Methylation profiling revealed four molecularly and clinically distinct PB subgroups, including two novel entities. Mutational and transcriptional analysis identified characteristic molecular features of each subgroup, such as mutations in the miRNA processing pathway or FOXR2 proto-oncogene overexpression. Furthermore, subgroups exhibited differences in propensity for metastasis, cytogenetics, and clinical outcomes. To dissect PB developmental origins and resolve PB subgroup biology, we have employed a combination of single-cell genomics and genetically engineered mouse modeling. We created a single-cell transcriptional atlas of the developing murine pineal gland across 11 timepoints and are currently integrating these data with single nuclei RNA-seq data of human PB (n=25). Single-cell analysis of the developing pineal gland revealed three distinct populations of pinealocytes, referred to as early, mid and late pinealocytes, which segregate by developmental stage yet lie along a single developmental trajectory. Preliminary results implicate significant associations between PBs and the early pinealocyte population as well as subgroup-specific differences in intratumoral heterogeneity. Furthermore, this knowledge has informed the downstream generation of biologically faithful disease models, including a transgenic mouse model of the PB-RB subgroup. Remarkably, this model shows up-regulation of key markers of PB such as Crx, Asmt and Otx2 and substantiates early pinealocytes as the probable cell-of-origin for this PB subgroup.

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