Biology subjects

Pincus, Z.

Publications and source records attributed to Pincus, Z..

5 recordsLinked to original sources

bioRxiv2024

Six drivers of aging identified among genes differentially expressed with age

Many studies have compared gene expression in young and old samples to gain insights on aging, the primary risk factor for most major chronic diseases. However, these studies only describe associations, failing to distinguish drivers of aging from compensatory geroprotective responses and incidental downstream effects. Here, we introduce a workflow to characterize the causal effects of differentially expressed genes on lifespan. First, we performed a meta-analysis of 25 gene expression datasets comprising samples of various tissues from healthy, untreated adult mammals (humans, dogs, and rodents) at two distinct ages. We ranked each gene according to the number of distinct datasets in which the gene was differentially expressed with age in a consistent direction. The top age-upregulated genes were TMEM176A, EFEMP1, CP, and HLA-A; the top age-downregulated genes were CA4, SIAH, SPARC, and UQCR10. Second, the effects of the top ranked genes on lifespan were measured by applying post-developmental RNA interference of the corresponding ortholog in the nematode C. elegans (two trials, with roughly 100 animals per genotype per trial). Out of 10 age-upregulated and 9 age-downregulated genes that were tested, two age-upregulated genes (csp-3/CASP1 and spch-2/RSRC1) and four age-downregulated genes (C42C1.8/DIRC2, ost-1/SPARC, fzy-1/CDC20, and cah-3/CA4) produced significant and reproducible lifespan extension. Notably, the data do not suggest that the direction of differential expression with age is predictive of the effect on lifespan. Our study provides novel insight into the relationship between differential gene expression and aging phenotypes, pilots an unbiased workflow that can be easily repeated and expanded, and pinpoints six genes with evolutionarily conserved, causal roles in the aging process for further study. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=169 HEIGHT=200 SRC="FIGDIR/small/606402v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@89cc31org.highwire.dtl.DTLVardef@bcd98eorg.highwire.dtl.DTLVardef@6f2b40org.highwire.dtl.DTLVardef@807e27_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2022

Automated identification and registration of anatomical landmarks in C. elegans

The physiology of the nematode C. elegans can be visualized with many microscopy techniques. However, quantitative microscopy of C. elegans is complicated by the flexible and deformable nature of the nematode. These differences in posture and shape must be addressed in some fashion in any automated or manual analysis. Manual approaches are time intensive and require hand-labeling anatomical regions of interest. Automated tools exist, but generally rely on high-magnification imaging using labeled nuclei as fiducial markers. Here we describe a suite of new tools that allows for high-throughput analysis of whole-body images, aligned using anatomical landmarks identified from brightfield images. We show how these tools can be used in basic morphometric tasks and examine anatomical variation and morphological changes in a population over time.

bioinformatics↗

bioRxiv2021

High temporal resolution measurements of movement reveal novel early-life physiological decline in C. elegans.

Age-related physiological changes are most notable and best-studied late in life, while the nature of aging in early- or middle-aged individuals has not been explored as thoroughly. In C. elegans, studies of movement vs. age generally delineate three distinct phases: sustained, youthful movement; a discrete onset of rapidly progressing impairment; and gross immobility. We investigated whether this first period of early-life adult movement is simply a sustained "healthy" level of high function followed by a discrete "movement catastrophe" -- or whether there are early-life changes in movement that precede future physiological declines. To determine how movement varies during early adult life, we followed isolated individuals throughout life with a previously unachieved combination of duration and temporal resolution. By tracking individuals across the first six days of adulthood, we observed declines in movement starting as early as the first two days of adult life, as well as high interindividual variability in total daily movement. These findings suggest that movement is a highly dynamic behavior early in life, and that factors driving movement decline may begin acting as early as the first day of adulthood. Using simulation studies based on acquired data, we suggest that too infrequent sampling in common movement assays limits observation of early-adult changes in motility, and we propose feasible alternate strategies and a framework for designing assays with increased sensitivity for early movement declines.

animal behavior and cognition↗

bioRxiv2021

Modular effects of gene promoters and chromatin environments on noise in gene expression.

Genetically identical cells growing in the same environment can have large differences in gene expression. Both locally acting cis-regulatory sequences (CRS) and the regional properties of chromosomal environments influence the noisiness of a genes expression. Whether or not local CRS and regional chromosomal environments act independently on noise, or whether they interact in complex ways is unknown. To address this question, we measured the expression mean and noise of reporter genes driven by different CRS at multiple chromosomal locations. While a strong power law relationship between mean expression and noise explains ~60% of noise for diverse promoters across chromosomal locations, modeling the residual mean-independent noise suggests that chromosomal environments have strong effects on expression noise by influencing how quickly genes transition from their inactive states to their active states and that the effects of local CRS and regional chromatin on noise are largely independent. Our results support a modular genome in which regional chromatin modifies the inherent relationship between the mean and noise of expression regardless of the identity of the promoter sequence.

systems biology↗

bioRxiv2018

Constriction rate modulation can drive cell size control and homeostasis in C. crescentus

Rod-shaped bacteria typically grow first via sporadic and dispersed elongation along their lateral walls, then via a combination of zonal elongation and constriction at the division site to form the poles of daughter cells. Although constriction comprises up to half of the cell cycle, its impact on cell size control and homeostasis has rarely been considered. To reveal the roles of cell elongation and constriction in bacterial size regulation during cell division, we captured the shape dynamics of Caulobacter crescentus with time-lapse structured illumination microscopy and used molecular markers as cell-cycle landmarks. We perturbed constriction rate using a hyperconstriction mutant or fosfomycin inhibition. We report that constriction rate contributes to both size control and homeostasis, by determining elongation during constriction, and by compensating for variation in pre-constriction elongation on a single-cell basis.

biophysics↗