scholarly journals Genome instability: a conserved mechanism of ageing?

2017 ◽  
Vol 61 (3) ◽  
pp. 305-315 ◽  
Author(s):  
Jan Vijg ◽  
Xiao Dong ◽  
Brandon Milholland ◽  
Lei Zhang
Keyword(s):  
Mutation Rate ◽  
Genome Instability ◽  
Single Cells ◽  
Somatic Cells ◽  
Cell Types ◽  
Base Substitution ◽  
Age Related ◽  
First Results ◽  
Substitution Mutations ◽  
Multicellular Organisms

DNA is the carrier of genetic information and the primary template from which all cellular information is ultimately derived. Changes in the DNA information content through mutation generate diversity for evolution through natural selection but are also a source of deleterious effects. It has since long been hypothesized that mutation accumulation in somatic cells of multicellular organisms could causally contribute to age-related cellular degeneration and death. Assays to detect different types of mutations, from base substitutions to large chromosomal aberrations, have been developed and show unequivocally that mutations accumulate in different tissues and cell types of ageing humans and animals. More recently, next-generation sequencing-based methods have been developed to accurately determine the complete landscape of base substitution mutations in single cells. The first results show that the somatic mutation rate is much higher than the germline mutation rate and that base substitution loads in somatic cells are high enough to potentially affect cellular function.

The developmentally regulated ECM glycoprotein ISG plays an essential role in organizing the ECM and orienting the cells of Volvox

2000 ◽  
Vol 113 (24) ◽  
pp. 4605-4617
Author(s):  
A. Hallmann ◽  
D.L. Kirk
Keyword(s):  
Critical Role ◽  
Somatic Cells ◽  
Cell Types ◽  
Model System ◽  
Swimming Behavior ◽  
Truncated Form ◽  
Developmentally Regulated ◽  
Gene Encoding ◽  
Ecm Architecture ◽  
Multicellular Organisms

Volvox is one of the simplest multicellular organisms with only two cell types, yet it has a surprisingly complex extracellular matrix (ECM) containing many region-specific morphological components, making Volvox suitable as a model system for ECM investigations. ECM deposition begins shortly after inversion, which is the process by which the embryo turns itself right-side-out at the end of embryogenesis. It was previously shown that the gene encoding an ECM glycoprotein called ISG is transcribed very transiently during inversion. Here we show that the developmentally controlled ISG accumulates at the bases of the flagella right after inversion, before any morphologically recognizable ECM structures have yet developed. Later, ISG is abundant in the ‘flagellar hillocks’ that encircle the basal ends of all flagella, and in the adjacent ‘boundary zone’ that delimits the spheroid. Transgenic Volvox were generated which express a truncated form of ISG. These transgenics exhibit a severely disorganized ECM within which the cells are embedded in a highly chaotic manner that precludes motility. A synthetic version of the C-terminal decapeptide of ISG has a similar disorganizing effect, but only when it is applied during or shortly after inversion. We postulate that ISG plays a critical role in morphogenesis and acts as a key organizer of ECM architecture; at the very beginning of ECM formation ISG establishes an essential initial framework that both holds the somatic cells in an adaptive orientation and acts as the scaffold upon which the rest of the ECM can be properly assembled, assuring that somatic cells of post-inversion spheroids are held in orientations and locations that makes adaptive swimming behavior possible.

scholarly journals The Heterocyst-Specific NsiR1 Small RNA Is an Early Marker of Cell Differentiation in Cyanobacterial Filaments

mBio ◽  
2014 ◽  
Vol 5 (3) ◽  
Author(s):  
Alicia M. Muro-Pastor
Keyword(s):  
Small Rna ◽  
Single Cells ◽  
Nitrogen Deficiency ◽  
Cell Types ◽  
Nitrogen Fixing ◽  
Vegetative Cells ◽  
Early Marker ◽  
Multicellular Organisms ◽  
Pcc 7120 ◽  
Different Cell Types

ABSTRACT Differentiation of single cells along filaments of cyanobacteria constitutes one of the simplest developmental patterns in nature. In response to nitrogen deficiency, certain cells located in a semiregular pattern along filaments differentiate into specialized nitrogen-fixing cells called heterocysts. The process involves the sequential activation of many genes whose expression takes place, either exclusively or at least more strongly, in those cells undergoing differentiation. In the model cyanobacterium Anabaena (Nostoc) sp. strain PCC 7120, increased transcription of hetR, considered the earliest detectable heterocyst-specific transcript, has been reported to occur in pairs or even in clusters of cells, thus making it difficult to identify prospective heterocysts during the early stages of differentiation, before any morphological change is detectable. The promoter of nsiR1 (nitrogen stress inducible RNA1), a heterocyst-specific small RNA, constitutes a minimal sequence promoting heterocyst-specific transcription. Using confocal fluorescence microscopy, I have analyzed expression of a gfp reporter transcriptionally fused to P nsiR1 . The combined analysis of green fluorescence (reporting transcriptional activity from P nsiR1 ) and red fluorescence (an indication of progress in the differentiation of individual cells) shows that expression of P nsiR1 takes place in single cells located in a semiregular pattern before any other morphological or fluorescence signature of differentiation can be observed, thus providing an early marker for cells undergoing differentiation. IMPORTANCE Cyanobacterial filaments containing heterocysts constitute an example of bacterial division of labor. When using atmospheric nitrogen, these filaments behave as multicellular organisms in which two different cell types (vegetative cells and nitrogen-fixing heterocysts) coexist and cooperate to achieve growth of the filament as a whole. The molecular basis governing the differentiation of individual vegetative cells, and thus the establishment of a one-dimensional pattern from cells that are apparently the same, remains one of the most intriguing aspects of this differentiation process. Recent evidence suggests that, at any given time, some cells in the filaments are more likely than others to become heterocysts when nitrogen limitation is encountered. The robust heterocyst-specific nsiR1 promoter, which is induced very early during differentiation, provides a valuable tool to analyze issues such as early candidacy or the possible role of transcriptional noise in determining the fate of specific cells in cyanobacterial filaments.

scholarly journals The genetic basis for the evolution of soma: mechanistic evidence for the co-option of a stress-induced gene into a developmental master regulator

2020 ◽  
Vol 287 (1940) ◽  
pp. 20201414
Author(s):  
Stephan G. König ◽  
Aurora M. Nedelcu
Keyword(s):  
Cell Fate ◽  
Stress Responses ◽  
Regulatory Gene ◽  
Somatic Cells ◽  
Cell Types ◽  
Volvox Carteri ◽  
Developmentally Regulated ◽  
Evolutionary Origins ◽  
Increased Sensitivity ◽  
Multicellular Organisms

In multicellular organisms with specialized cells, the most significant distinction among cell types is between reproductive (germ) cells and non-reproductive/somatic cells (soma). Although soma contributed to the marked increase in complexity of many multicellular lineages, little is known about its evolutionary origins. We have previously suggested that the evolution of genes responsible for the differentiation of somatic cells involved the co-option of life history trade-off genes that in unicellular organisms enhanced survival at a cost to immediate reproduction. In the multicellular green alga, Volvox carteri , cell fate is established early in development by the differential expression of a master regulatory gene known as regA . A closely related RegA -Like Sequence ( RLS1 ) is present in its single-celled relative, Chlamydomonas reinhardtii . RLS1 is expressed in response to stress, and we proposed that an environmentally induced RLS1 -like gene was co-opted into a developmental pathway in the lineage leading to V. carteri . However, the exact evolutionary scenario responsible for the postulated co-option event remains to be determined. Here, we show that in addition to being developmentally regulated, regA can also be induced by environmental cues, indicating that regA has maintained its ancestral regulation. We also found that the absence of a functional RegA protein confers increased sensitivity to stress, consistent with RegA having a direct or indirect role in stress responses. Overall, this study (i) provides mechanistic evidence for the co-option of an environmentally induced gene into a major developmental regulator, (ii) supports the view that major morphological innovations can evolve via regulatory changes and (iii) argues for the role of stress in the evolution of multicellular complexity.

scholarly journals The Matrisome during Aging and Longevity: A Systems-Level Approach towards Defining Matreotypes Promoting Healthy Aging

2019 ◽  
Author(s):  
Collin Ewald
Keyword(s):  
Healthy Aging ◽  
Physiological State ◽  
Cell Types ◽  
Physiological Status ◽  
Ecm Proteins ◽  
Age Related ◽  
Accumulation Of Damage ◽  
Cellular Identity ◽  
Multicellular Organisms ◽  
Cellular Components

Accumulation of damage is generally considered the cause of aging. Interventions that delay aging mobilize mechanisms that protect and repair cellular components. Consequently, research has been focused on studying the protective and homeostatic mechanisms within cells. However, in humans and other multicellular organisms, cells are surrounded by extracellular matrices (ECM), which are important for tissue structure, function and intercellular communication. During aging, components of the ECM become damaged through fragmentation, glycation, crosslinking, and accumulation of protein aggregation, all of which contribute to age-related pathologies. Interestingly, placing senescent cells into a young ECM rejuvenates them and we found that many longevity-assurances pathways re-activate de-novosynthesis of ECM proteins during aging. This raises the question of what constitutes a young ECM to reverse aging or maintain health? In order to make inroads to answering this question, I suggest a systems-level approach of quantifying the matrisome or ECM compositions reflecting health, pathology, or phenotype and propose a novel term, the “matreotype”, to describe this. The matreotype is defined as the composition and modification of ECM or matrisome proteins associated with or caused by a phenotype, such as longevity, or a distinct and acute physiological state, as observed during aging or disease. Every cell type produces its unique ECM. Interestingly, cancer-cell types can even be identified based on their unique ECM composition. Thus, the matreotype reflects cellular identity and physiological status. Defined matreotypes could be used as biomarkers or prognostic factors for disease or health status during aging with potential relevance for personalized medicine. Treatment with biologics that alter ECM-to-cell mechanotransduction might be a strategy to reverse age-associated pathologies. An understanding of how to reverse from an old to a young matreotype might point towards novel strategies to rejuvenate cells and help maintain tissue homeostasis to promote health during aging.

scholarly journals Evolution of the mutational process under relaxed selection in Caenorhabditis elegans

2018 ◽  
Author(s):  
Ayush Shekhar Saxena ◽  
Matthew P. Salomon ◽  
Chikako Matsuba ◽  
Shu-Dan Yeh ◽  
Charles F. Baer
Keyword(s):  
Caenorhabditis Elegans ◽  
Mutation Rate ◽  
Tandem Repeats ◽  
Gc Content ◽  
Base Substitution ◽  
Rate Variation ◽  
High Fitness ◽  
Multicellular Organisms ◽  
Mutational Process ◽  
Short Tandem

AbstractThe mutational process varies at many levels, from within genomes to among taxa. Many mechanisms have been linked to variation in mutation, but understanding of the evolution of the mutational process is rudimentary. Physiological condition is often implicated as a source of variation in microbial mutation rate and may contribute to mutation rate variation in multicellular organisms.Deleterious mutations are a ubiquitous source of variation in condition. We test the hypothesis that the mutational process depends on the underlying mutation load in two groups of Caenorhabditis elegans mutation accumulation (MA) lines that differ in their starting mutation loads. “First-Order MA” (O1MA) lines maintained under minimal selection for ∼250 generations were divided into high-fitness and low-fitness groups and sets of “second-order MA” (O2MA) lines derived from each O1MA line were maintained for ∼150 additional generations. Genomes of 48 O2MA lines and their progenitors were sequenced. There is significant variation among O2MA lines in base-substitution rate (µbs), but no effect of initial fitness, whereas the indel rate is greater in high-fitness O2MA lines. Overall, µbs is positively correlated with recombination and proximity to short tandem repeats and negatively correlated with 10 bp and 1 Kb GC content. However, probability of mutation is well-predicted by the three-nucleotide motif. ∼90% of the variance in standing nucleotide variation is explained by mutability. Total mutation rate increased in the O2MA lines, as predicted by the “drift barrier” model of mutation rate evolution. These data, combined with experimental estimates of fitness, suggest that epistasis is synergistic.

scholarly journals Low base-substitution mutation rate in the germline genome of the ciliate Tetrahymena thermophila

2015 ◽  
Author(s):  
Hongan Long ◽  
David J. Winter ◽  
Allan Y.-C Chang ◽  
Way Sung ◽  
Steven H. Wu ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Tetrahymena Thermophila ◽  
Mutation Rates ◽  
Base Substitution ◽  
Paramecium Tetraurelia ◽  
Epigenetic Factors ◽  
Detection Approach ◽  
Evolution Experiment ◽  
Substitution Mutations ◽  
Substitution Mutation

AbstractMutation is the ultimate source of all genetic variation and is, therefore, central to evolutionary change. Previous work on Paramecium tetraurelia found an unusually low germline base-substitution mutation rate in this ciliate. Here, we tested the generality of this result among ciliates using Tetrahymena thermophila. We sequenced the genomes of 10 lines of T. thermophila that had each undergone approximately 1,000 generations of mutation accumulation (MA). We applied an existing mutation-calling pipeline and developed a new probabilistic mutation detection approach that directly models the design of an MA experiment and accommodates the noise introduced by mismapped reads. Our probabilistic mutation-calling method provides a straightforward way of estimating the number of sites at which a mutation could have been called if one was present, providing the denominator for our mutation rate calculations. From these methods, we find that T. thermophila has a germline base-substitution mutation rate of 7.61 × 10−12 per site, per cell division, which is consistent with the low base-substitution mutation rate in P. tetraurelia. Over the course of the evolution experiment, genomic exclusion lines derived from the MA lines experienced a fitness decline that cannot be accounted for by germline base-substitution mutations alone, suggesting that other genetic or epigenetic factors must be involved. Because selection can only operate to reduce mutation rates based upon the “visible” mutational load, asexual reproduction with a transcriptionally silent germline may allow ciliates to evolve extremely low germline mutation rates.

Role of Transcriptional Read-Through in PRE Activity in Drosophila melanogaster

Acta Naturae ◽  
2016 ◽  
Vol 8 (2) ◽  
pp. 79-86 ◽  
Author(s):  
P. V. Elizar’ev ◽  
D. V. Lomaev ◽  
D. A. Chetverina ◽  
P. G. Georgiev ◽  
M. M. Erokhin
Keyword(s):  
Dna Sequences ◽  
Cell Types ◽  
Transcription Terminator ◽  
Response Elements ◽  
Polycomb Response Elements ◽  
The Individual ◽  
Multicellular Organisms ◽  
Different Cell Types ◽  
Main Factor

Maintenance of the individual patterns of gene expression in different cell types is required for the differentiation and development of multicellular organisms. Expression of many genes is controlled by Polycomb (PcG) and Trithorax (TrxG) group proteins that act through association with chromatin. PcG/TrxG are assembled on the DNA sequences termed PREs (Polycomb Response Elements), the activity of which can be modulated and switched from repression to activation. In this study, we analyzed the influence of transcriptional read-through on PRE activity switch mediated by the yeast activator GAL4. We show that a transcription terminator inserted between the promoter and PRE doesnt prevent switching of PRE activity from repression to activation. We demonstrate that, independently of PRE orientation, high levels of transcription fail to dislodge PcG/TrxG proteins from PRE in the absence of a terminator. Thus, transcription is not the main factor required for PRE activity switch.

scholarly journals Single Cell Genetic Profiling of Tumors of Breast Cancer Patients Aged 50 Years and Older Reveals Enormous Intratumor Heterogeneity Independent of Individual Prognosis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3366
Author(s):  
Anna-Sophie Liegmann ◽  
Kerstin Heselmeyer-Haddad ◽  
Annette Lischka ◽  
Daniela Hirsch ◽  
Wei-Dong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Copy Number ◽  
Genome Instability ◽  
Single Cells ◽  
Gene Mutations ◽  
Intratumor Heterogeneity ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Pik3ca Mutations

Purpose: Older breast cancer patients are underrepresented in cancer research even though the majority (81.4%) of women dying of breast cancer are 55 years and older. Here we study a common phenomenon observed in breast cancer which is a large inter- and intratumor heterogeneity; this poses a tremendous clinical challenge, for example with respect to treatment stratification. To further elucidate genomic instability and tumor heterogeneity in older patients, we analyzed the genetic aberration profiles of 39 breast cancer patients aged 50 years and older (median 67 years) with either short (median 2.4 years) or long survival (median 19 years). The analysis was based on copy number enumeration of eight breast cancer-associated genes using multiplex interphase fluorescence in situ hybridization (miFISH) of single cells, and by targeted next-generation sequencing of 563 cancer-related genes. Results: We detected enormous inter- and intratumor heterogeneity, yet maintenance of common cancer gene mutations and breast cancer specific chromosomal gains and losses. The gain of COX2 was most common (72%), followed by MYC (69%); losses were most prevalent for CDH1 (74%) and TP53 (69%). The degree of intratumor heterogeneity did not correlate with disease outcome. Comparing the miFISH results of diploid with aneuploid tumor samples significant differences were found: aneuploid tumors showed significantly higher average signal numbers, copy number alterations (CNAs) and instability indices. Mutations in PIKC3A were mostly restricted to luminal A tumors. Furthermore, a significant co-occurrence of CNAs of DBC2/MYC, HER2/DBC2 and HER2/TP53 and mutual exclusivity of CNAs of HER2 and PIK3CA mutations and CNAs of CCND1 and PIK3CA mutations were revealed. Conclusion: Our results provide a comprehensive picture of genome instability profiles with a large variety of inter- and intratumor heterogeneity in breast cancer patients aged 50 years and older. In most cases, the distribution of chromosomal aneuploidies was consistent with previous results; however, striking exceptions, such as tumors driven by exclusive loss of chromosomes, were identified.

scholarly journals The landscape of alternative polyadenylation in single cells of the developing mouse embryo

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Vikram Agarwal ◽  
Sereno Lopez-Darwin ◽  
David R. Kelley ◽  
Jay Shendure
Keyword(s):  
Rna Binding ◽  
Developmental Stages ◽  
Single Cells ◽  
Neuronal Cell ◽  
Alternative Polyadenylation ◽  
Cell Types ◽  
Untranslated Regions ◽  
Mammalian Development ◽  
Translation Rate ◽  
Dynamic Landscape

Abstract3′ untranslated regions (3′ UTRs) post-transcriptionally regulate mRNA stability, localization, and translation rate. While 3′-UTR isoforms have been globally quantified in limited cell types using bulk measurements, their differential usage among cell types during mammalian development remains poorly characterized. In this study, we examine a dataset comprising ~2 million nuclei spanning E9.5–E13.5 of mouse embryonic development to quantify transcriptome-wide changes in alternative polyadenylation (APA). We observe a global lengthening of 3′ UTRs across embryonic stages in all cell types, although we detect shorter 3′ UTRs in hematopoietic lineages and longer 3′ UTRs in neuronal cell types within each stage. An analysis of RNA-binding protein (RBP) dynamics identifies ELAV-like family members, which are concomitantly induced in neuronal lineages and developmental stages experiencing 3′-UTR lengthening, as putative regulators of APA. By measuring 3′-UTR isoforms in an expansive single cell dataset, our work provides a transcriptome-wide and organism-wide map of the dynamic landscape of alternative polyadenylation during mammalian organogenesis.

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