Biology subjects

Panchy, N.

Publications and source records attributed to Panchy, N..

6 recordsLinked to original sources

bioRxiv2022

Analysis of transcriptome datasets reveals involvement of epithelial-mesenchymal transition genes in small cell lung cancer phenotypic plasticity

Small cell lung cancer (SCLC) is an aggressive cancer recalcitrant to treatment, arising predominantly from epithelial pulmonary neuroendocrine (NE) cells. Intra-tumor heterogeneity plays critical roles in SCLC disease progression, metastasis and treatment resistance. At least five transcriptional SCLC NE and non-NE cell subtypes were recently defined by gene expression signatures. Transition from NE to non-NE cell states and cooperation between subtypes within a tumor likely contribute to SCLC progression by mechanisms of adaptation to perturbations. Therefore, gene regulatory programs distinguishing SCLC subtypes or promoting transitions are of great interest. Here, we systematically analyze the relationship between SCLC NE/non-NE transition and epithelial to mesenchymal transition (EMT)--a well-studied cellular process contributing to cancer invasiveness and resistance--using multiple transcriptome datasets from SCLC mouse tumor models, human cancer cell lines and tumor samples. The NE SCLC-A2 subtype maps to the epithelial state. In contrast, SCLC-A and SCLC-N (NE) map to a mesenchymal state (M1) that is distinct from the non-NE mesenchymal state (M2). The correspondence between SCLC subtypes and the EMT program paves the way for further work to understand gene regulatory mechanisms of SCLC tumor plasticity with applicability to other cancer types.

cancer biology↗

bioRxiv2022

Comparative single-cell transcriptomes of dose and time dependent epithelial-mesenchymal spectrums

Epithelial-mesenchymal transition (EMT) is a cellular process involved in development and disease progression. Intermediate EMT states were observed in tumors and fibrotic tissues, but previous in vitro studies focused on time-dependent responses with single doses of signals; it was unclear whether single-cell transcriptomes support stable intermediates observed in diseases. Here, we performed single-cell RNA-sequencing with human mammary epithelial cells treated with multiple doses of TGF-{beta}. We found that dose-dependent EMT harbors multiple intermediate states at nearly steady state. Comparisons of dose- and time-dependent EMT transcriptomes revealed that the dose-dependent data enable higher sensitivity to detect genes associated EMT. We identified cell clusters unique to time-dependent EMT, reflecting cells en route to stable states. Combining dose- and time-dependent cell clusters gave rise to accurate prognosis for cancer patients. Our transcriptomic data and analyses uncover a stable EMT continuum at the single-cell resolution, and complementary information of two types of single-cell experiments.

genomics↗

bioRxiv2021

Selection-Enriched Genomic Loci (SEGL) Reveals Genetic Loci for Environmental Adaptation and Photosynthetic Productivity in Chlamydomonas reinhardtii.

This work demonstrates an approach to produce and select hybrid algal strains exhibiting increased photosynthetic productivity under multiple environmental conditions. This simultaneously addresses two major impediments to improving algal bioenergy production: 1) generating new genetic variants with improved performance; and 2) disentangling complex interactions between genetic and physiological factors contributing to these improvements. We pooled progeny generated from mating two environmental isolates of the green alga Chlamydomonas reinhardtii and cultured the pools under multiple environmental conditions. Strains from the outcompeting populations showed substantial (in some cases over 3 fold) increases in productivity over the parental lines under certain environments related to biomass production, including laboratory conditions as well as hyperoxia, fluctuating light, high salinity and high temperature. The results indicate that C. reinhardtii has remarkable, untapped, directed evolution capacity that may be harnessed using breeding and competition approaches. The populations were deep sequenced at multiple time points to identify "Selection-Enriched Genomic Loci" (SEGL) that accumulated in the populations, and thus likely confer increased fitness under the respective environmental conditions. With improved resolution, SEGL mapping can identify allelic combinations used for targeted breeding approaches, generating elite algal lines with multiple desirable traits, as well as to further understand the genetic and mechanistic bases of photosynthetic productivity. Significance StatementIncreasing the photosynthetic efficiency of algae during biomass production is perhaps the most critical hurdle for economically sustainable algal based biofuels. This presents unique challenges because modifications designed to increase photosynthesis often result in decreased fitness, due to production of toxic reactive oxygen species when photosynthesis is not adequately regulated. These problems are exacerbated under natural and outdoor production environments because of the complex nature of photosynthesis and the multifaceted interactions between genetic, environmental and physiological factors. Here, we demonstrate a high throughput biotechnological screening approach that simultaneously produces algal strains with highly increased autotrophic productivity and identifies genomic loci contributing to these improvements. Our results demonstrate that Chlamydomonas reinhardtii exhibits high directed evolutionary capacity readily accessed through breeding and selection.

evolutionary biology↗

bioRxiv2020

Early detection of daylength variations with a feedforward circuit co-regulated by circadian rhythm and diel light-dark cycle

Light-entrained circadian clocks confer rhythmic dynamics of cellular and molecular activities to animals and plants. These intrinsic clocks allow stable anticipations to light-dark (diel) cycles. Many genes in the model plant Arabidopsis thaliana are regulated by diel cycles via pathways independent of the clock, suggesting that the integration of circadian and light signals is important for the fitness of plants. Previous studies of light-clock signal integrations have focused on moderate phase adjustment of the two signals. However, dynamical features of integrations across a broad range of phases remain elusive. We recently found that phosphorylation of RIBOSOMAL PROTEIN OF THE SMALL SUBUNIT 6 (RPS6 or eS6), a ubiquitous post-translational modification across kingdoms, is influenced by the circadian clock and the light-dark (diel) cycle in an opposite manner. In order to understand this striking phenomenon and its underlying information processing capabilities, we built a mathematical model for the eS6-P control circuit. We found that the dynamics of eS6-P can be explained by a feedforward circuit with inputs from both circadian and diel cycles. Furthermore, the early-day response of this circuit with dual rhythmic inputs is sensitive to the changes in daylength, including both transient and gradual changes observed in realistic light intervals across a year, due to weather and seasons. By analyzing published gene expression data, we found that the dynamics produced by the eS6-P control circuit can be observed in the expression profiles of a large number of genes. Our work provides mechanistic insights into the complex dynamics of a ribosomal protein, and it proposes a previously underappreciated function of the circadian clock which not only prepares organisms for normal diel cycles but also helps to detect both transient and seasonal changes with a predictive power.

systems biology↗

bioRxiv2019

Combinatorial perturbation analysis reveals divergent regulations of mesenchymal genes during epithelial-to-mesenchymal transition

Epithelial-to-mesenchymal transition (EMT), a fundamental transdifferentiation process in development, produces diverse phenotypes in different physiological or pathological conditions. Many genes involved in EMT have been identified to date, but mechanisms contributing to the phenotypic diversity and those governing the coupling between the dynamics of epithelial (E) genes and that of the mesenchymal (M) genes are unclear. In this study, we employed combinatorial perturbations to mammary epithelial cells to induce a series of EMT phenotypes by manipulating two essential EMT-inducing elements, namely TGF-{beta} and ZEB1. By measuring transcriptional changes in more than 700 E- and M-genes, we discovered that the M-genes exhibit a significant diversity in their dependency to these regulatory elements and identified three groups of M-genes that are controlled by different regulatory circuits. Notably, functional differences were detected among the M-gene clusters in motility regulation and in survival of breast cancer patients. We computationally predicted and experimentally confirmed that the reciprocity and reversibility of EMT are jointly regulated by ZEB1. Our integrative analysis reveals the key roles of ZEB1 in coordinating the dynamics of a large number of genes during EMT, and it provides new insights into the mechanisms for the diversity of EMT phenotypes.

systems biology↗

bioRxiv2017

Regulatory Divergence In Wound-Responsive Gene Expression In Domesticated And Wild Tomato

BackgroundThe evolution of cis- and trans-regulatory components of transcription is central to how stress response and tolerance differ across species. However, it remains largely unknown how divergence in TF binding specificity and cis-regulatory sites contribute to the divergence of stress-responsive gene expression between wild and domesticated species.\n\nResultsUsing tomato as model, we analyzed the transcriptional profile of wound-responsive genes in wild Solanum pennellii and domesticated S. lycopersicum. We found that extensive expression divergence of wound-responsive genes is associated with speciation. To assess the degree of trans-regulatory divergence between these two species, 342 and 267 putative cis-regulatory elements (pCREs) in S. lycopersicum and S. pennellii, respectively, were identified that were predictive of wound-induced gene expression. We found that 35-66% of pCREs were conserved across species, suggesting that the remaining proportion (34-65%) of pCREs are species specific. This finding indicates a substantially higher degree of trans-regulatory divergence between these two plant species, which diverged [~]3-7 million years ago, compared to that observed in mouse and human, which diverged [~]100 million years ago. In addition, differences in pCRE sites were significantly associated with differences in wound-responsive gene expression between wild and domesticated tomato orthologs, suggesting the presence of substantial cis-regulatory divergence.\n\nConclusionsOur study provides new insights into the mechanistic basis of how the transcriptional response to wounding is regulated and, importantly, the contribution of cis- and trans-regulatory components to variation in wound-responsive gene expression during species domestication.

evolutionary biology↗