Biology subjects

Findley, A.

Publications and source records attributed to Findley, A..

4 recordsLinked to original sources

bioRxiv2026

RE-1 silencing transcription factor is reduced in endometriosis and uterine deletion in mice alters progesterone responsiveness

Endometriosis is a steroid-dependent gynecologic disease characterized by progesterone (P4) resistance, subfertility/infertility, and pelvic pain; however, the molecular mechanisms underlying impaired P4 responsiveness in endometriosis tissue are not fully understood. RE-1 silencing transcription factor (REST), a transcriptional regulator implicated in steroid hormone signaling, has emerged as a potential mediator of P4 responsiveness. Here, we investigated the role of REST in endometriosis using human tissues and a uterine-specific Rest conditional knockout mouse model. Immunohistochemical analysis of eutopic endometrium and ectopic lesions from patients with endometriosis revealed significantly reduced nuclear REST expression compared with control endometrium, suggesting loss of functional REST in disease. To assess the physiological consequences of REST deficiency, uterine-specific Rest knockout (Rest d/d) mice were generated. Rest d/d females exhibited progressive subfertility and hyper-estrogenic uterine tissue characteristics that displayed a blunted responsiveness to P4 treatment. Loss of Rest selectively altered expression of P4-responsive genes associated with endometriosis pathology, despite preserved P4 receptor expression. Following induction of experimental endometriosis, female mice that developed endometriotic-like lesions using Rest-deficient donor tissue developed significantly larger lesions that were less responsive to P4 treatment compared to lesions induced using control tissue. Mechanical sensitivity was modestly increased in mice receiving Rest-deficient tissue, whereas vaginal hyperalgesia was unaffected. These findings identify loss of nuclear REST as a feature of endometriosis and support a role of REST in subfertility, lesion progression, and blunted response to P4. REST may represent a novel molecular contributor to altered P4 responsiveness and a potential therapeutic target in endometriosis. Significance StatementEndometriosis is a common disease in women characterized by altered steroid hormone signaling, infertility, and pelvic pain. RE-1 silencing transcription factor (REST) is a candidate regulator of steroid hormone signaling in gynecologic disease but a role in endometriosis pathophysiology remains unexplored. To fill this knowledge gap, our study utilizes human endometrial and endometriotic tissues coupled with a conditional knockout mouse model for uterine Rest deficiency. We show that REST is significantly reduced in eutopic and ectopic endometrial tissue from women with endometriosis and that deletion from mouse uterine tissue recapitulates clinical characteristics in women with endometriosis including progesterone resistance, sub-fertility and pelvic pain. These findings will further guide future research to understand impaired steroid signaling in the pathophysiology of endometriosis.

physiology↗

bioRxiv2021

A signature of Neanderthal introgression on molecular mechanisms of environmental responses

Ancient human migrations led to the settlement of population groups in varied environmental contexts worldwide. The extent to which adaptation to local environments has shaped human genetic diversity is a longstanding question in human evolution. Recent studies have suggested that introgression of archaic alleles in the genome of modern humans may have contributed to adaptation to environmental pressures such as pathogen exposure. Functional genomic studies have demonstrated that variation in gene expression across individuals and in response to environmental perturbations is a main mechanism underlying complex trait variation. We considered gene expression response to in vitro treatments as a molecular phenotype to identify genes and regulatory variants that may have played an important role in adaptations to local environments. We investigated if Neanderthal introgression in the human genome may contribute to the transcriptional response to environmental perturbations. To this end we used eQTLs for genes differentially expressed in a panel of 52 cellular environments, resulting from 5 cell types and 26 treatments, including hormones, vitamins, drugs, and environmental contaminants. We found that SNPs with introgressed Neanderthal alleles (N-SNPs) disrupt binding of transcription factors important for environmental responses, including ionizing radiation and hypoxia, and for glucose metabolism. We identified an enrichment for N-SNPs among eQTLs for genes differentially expressed in response to 8 treatments, including glucocorticoids, caffeine, and vitamin D. Using Massively Parallel Reporter Assays (MPRA) data, we validated the regulatory function of 21 introgressed Neanderthal variants in the human genome, corresponding to 8 eQTLs regulating 15 genes that respond to environmental perturbations. These findings expand the set of environments where archaic introgression may have contributed to adaptations to local environments in modern humans and provide experimental validation for the regulatory function of introgressed variants.

evolutionary biology↗

bioRxiv2018

circuitSNPs: Predicting genetic effects using a Neural Network to model regulatory modules of DNase-seq footprints

MotivationIdentifying and characterizing the function of non coding regions in the genome, and the genetic variants disrupting gene regulation, is a challenging question in genetics. Through the use of high throughput experimental assays that provide information about the chromatin state within a cell, coupled with modern computational approaches, much progress has been made towards this goal, yet we still lack a comprehensive characterization of the regulatory grammar. We propose a new method that combines sequence and chromatin accessibility information through a neural network framework with the goal of determining and annotating the effect of genetic variants on regulation of chromatin accessibility and gene transcription. Importantly, our new approach can consider multiple combinations of transcription factors binding at the same location when assessing the functional impact of non-coding genetic variation.\n\nResultsOur method, circuitSNPs, generates predictions describing the functional effect of genetic variants on local chromatin accessibility. Further, we demonstrate that circuitSNPs not only performs better than other variant annotation tools, but also retains the causal motifs / transcription factors that drive the predicted regulatory effect.\n\nContactfluca@wayne.edu, rpique@wayne.edu\n\nAvailabilityhttp://github.com/piquelab/circuitSNPs

bioinformatics↗

bioRxiv2017

Environmental Perturbations Lead To Extensive Directional Shifts In RNA Processing

Environmental perturbations have large effects on both organismal and cellular traits, including gene expression, but the extent to which the environment affects RNA processing remains largely uncharacterized. Recent studies have identified a large number of genetic variants associated with variation in RNA processing that also have an important role in complex traits; yet we do not know in which contexts the different underlying isoforms are used. Here, we comprehensively characterized changes in RNA processing events across 89 environments in five human cell types and identified 15,300 event shifts (FDR = 15%) comprised of eight event types in over 4,000 genes. Many of these changes occur consistently in the same direction across conditions, indicative of global regulation by trans factors. Accordingly, we demonstrate that environmental modulation of splicing factor binding predicts shifts in intron retention, and that binding of transcription factors predicts shifts in AFE usage in response to specific treatments. We validated the mechanism hypothesized for AFE in two independent datasets. Using ATAC-seq, we found altered binding of 64 factors in response to selenium at sites of AFE shift, including ELF2 and other factors in the ETS family. We also performed AFE QTL mapping in 373 individuals and found an enrichment for SNPs predicted to disrupt binding of the ELF2 factor. Together, these results demonstrate that RNA processing is dramatically changed in response to environmental perturbations through specific mechanisms regulated by trans factors.\n\nAuthor SummaryChanges in a cells environment and genetic variation have been shown to impact gene expression. Here, we demonstrate that environmental perturbations also lead to extensive changes in alternative RNA processing across a large number of cellular environments that we investigated. These changes often occur in a non-random manner. For example, many treatments lead to increased intron retention and usage of the downstream first exon. We also show that the changes to first exon usage are likely dependent on changes in transcription factor binding. We provide support for this hypothesis by considering how first exon usage is affected by disruption of binding due to treatment with selenium. We further validate the role of a specific factor by considering the effect of genetic variation in its binding sites on first exon usage. These results help to shed light on the vast number of changes that occur in response to environmental stimuli and will likely aid in understanding the impact of compounds to which we are daily exposed.

genomics↗