Biology subjects

Soifer, I.

Publications and source records attributed to Soifer, I..

5 recordsLinked to original sources

bioRxiv2022

Cost-efficient whole genome-sequencing using novel mostly natural sequencing-by-synthesis chemistry and open fluidics platform

We introduce a massively parallel novel sequencing platform that combines an open flow cell design on a circular wafer with a large surface area and mostly natural nucleotides that allow optical end-point detection without reversible terminators. This platform enables sequencing billions of reads with longer read length ([~]300bp) and fast runs times (<20hrs) with high base accuracy (Q30 > 85%), at a low cost of $1/Gb. We establish system performance by whole-genome sequencing of the Genome-In-A-Bottle reference samples HG001-7, demonstrating high accuracy for SNPs (99.6%) and Indels in homopolymers up to length 10 (96.4%) across the vast majority (>98%) of the defined high-confidence regions of these samples. We demonstrate scalability of the whole-genome sequencing workflow by sequencing an additional 224 selected samples from the 1000 Genomes project achieving high concordance with reference data.

genomics↗

bioRxiv2021

Revisiting the Hayflick Limit: Insights from an Integrated Analysis of Changing Transcripts, Proteins, Metabolites and Chromatin

The process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular aging in vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflicks original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by the transcription factors YAP1/TEAD1 and TGF-{beta}2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.

genomics↗

bioRxiv2018

The Miniature-chemostat Aging Device: A new experimental platform facilitates assessment of the transcriptional and chromatin landscapes of replicatively aging yeast

Replicative aging of Saccharomyces cerevisiae is an established model system for eukaryotic cellular aging. A major limitation in yeast lifespan studies has been the difficulty of separating old cells from young cells in large quantities for in-depth comparative analyses. We engineered a new platform, the Miniature-chemostat Aging Device (MAD), that enables purification of aged cells at sufficient quantities to enable genomic and biochemical characterization of aging yeast populations. Using the MAD platform, we measured DNA accessibility (ATAC-Seq) and gene expression (RNA-Seq) changes in aging cells. Our data highlight an intimate connection between aging, growth rate, and stress, as many (but not all) genes that change with age have altered expression in cells that are subjected to stress. Stress-independent genes that change with age are highly enriched for targets of the signal recognition particle (SRP). By obtaining pure populations of old cells, we find that nucleosome occupancy does not change significantly with age; however, significant age-dependent changes in accessibility at ~12% of genomic loci reflect decreased replication and changing activities of cell cycle and metabolic regulators. Finally, ATAC-seq revealed that upregulating the proteasome by deleting UBR2 reduces rDNA instability usually observed in aging cells, demonstrating a connection between proteasome activity and genomic stability.

systems biology↗

bioRxiv2017

Principles Of Cellular Resource Allocation Revealed By Condition-Dependent Proteome Profiling

Growing cells coordinate protein translation with metabolic rates. Central to this coordination is ribosome production. Ribosomes drive cell growth, but translation of ribosomal proteins competes with production of other proteins. Theory shows that cell growth is maximized when all expressed ribosomes are constantly translating. To examine whether budding yeast function at this limit of full ribosomal usage, we profiled the proteomes of cells growing in different environments. We find that cells produce an excess of ribosomal proteins, amounting to a constant {approx}8% of the proteome. Accordingly, {approx}25% of ribosomal proteins expressed in rapidly growing cells do not contribute to translation. This fraction increases as growth rate decreases. These excess ribosomal proteins are employed during nutrient upshift or when forcing unneeded expression. We suggest that steadily growing cells prepare for conditions that demand increased translation by producing excess ribosomes, at the expense of lower steady-state growth rate.

cell biology↗

bioRxiv2017

Large-scale rewiring in a yeast hybrid

The merging of genomes in inter-specific hybrids can result in novel phenotypes, including increased growth rate and biomass yield, a phenomenon known as heterosis. We describe a budding yeast hybrid that grows faster than its parents under different environments. Phenotypically, the hybrid progresses more rapidly through cell cycle checkpoints, relieves the repression of respiration in fast growing conditions, does not slow down its growth when presented with ethanol stress, and shows increasing signs of DNA damage. A systematic genetic screen identified hundreds of alleles affecting hybrid growth whose identity vastly differed between the hybrid and its parent and between growth conditions. This large-scale rewiring of allele effects suggests that despite showing clear heterosis, the hybrid is perturbed in multiple regulatory processes. We discuss the possibility that incompatibilities contribute to hybrid vigor by perturbing safeguard mechanisms that limit growth in the parental background.

systems biology↗