Biology subjects

Bresnick, E. H.

Publications and source records attributed to Bresnick, E. H..

5 recordsLinked to original sources

bioRxiv2025

Systematic Background Selection for Enhanced Contrastive Dimension Reduction

Contrastive dimension reduction enhances the analysis of high-dimensional data by generating target-specific low-dimensional representations relative to a background. Emerging methods for contrastive dimension reduction have demonstrated their utility in extracting target-specific signals across domains involving high-dimensional observations, including genomics, transcriptomics, and pattern recognition. However, even though choosing an appropriate background is critical to the success of contrastive dimension reduction, no established criterion currently exists for selecting such backgrounds. To address this gap, we introduce BasCoD, a novel testing framework grounded in the spectral theory of subspace inclusion, to enable rigorous evaluation and optimal selection of backgrounds. Extensive application of BasCoD across diverse single-cell datasets demonstrates its effectiveness in systematically identifying suitable backgrounds, thereby significantly improving the contrast and interpretability of the derived target representations. We further illustrate how BasCoD can facilitate design of appropriate backgrounds in large-scale single cell experiments under heterogeneous conditions.

genomics↗

bioRxiv2022

Epigenetic and Signaling Determinants of Blood-Brain Barrier-Regulatory Genetic Networks

The blood-brain barrier (BBB) controls the movement of molecules into and out of the central nervous system (CNS). Since a functional BBB forms by mouse embryonic day E15.5, we reasoned that gene cohorts expressed in CNS endothelial cells (EC) at E13.5 contribute to BBB formation. In contrast, adult gene signatures reflect BBB maintenance mechanisms. Supporting this hypothesis, transcriptomic analysis revealed distinct cohorts of EC genes involved in BBB formation and maintenance. Here, we demonstrate that epigenetic regulators histone deacetylase 2 (HDAC2) and polycomb repressive complex 2 (PRC2) control EC gene expression for BBB development and prevent Wnt/{beta}-catenin (Wnt) target genes from being expressed in adult CNS ECs. Low Wnt activity during development modifies BBB genes epigenetically for the formation of functional BBB. As a Class-I HDAC inhibitor induces adult CNS ECs to regain Wnt activity and BBB genetic signatures that support BBB formation, our results inform strategies to promote BBB repair.

neuroscience↗

bioRxiv2021

MLG: Multilayer graph clustering for multi-condition scRNA-seq data

Single-cell transcriptome sequencing (scRNA-seq) enabled investigations of cellular heterogeneity at exceedingly higher resolutions. Identification of novel cell types or transient developmental stages across multiple experimental conditions is one of its key applications. Linear and non-linear dimensionality reduction for data integration became a foundational tool in inference from scRNA-seq data. We present Multi Layer Graph Clustering (MLG) as an integrative approach for combining multiple dimensionality reduction of multi-condition scRNA-seq data. MLG generates a multilayer shared nearest neighbor cell graph with higher signal-to-noise ratio and outperforms current best practices in terms of clustering accuracy across large-scale bench-marking experiments. Application of MLG to a wide variety of datasets from multiple conditions highlights how MLG boosts signal-to-noise ratio for fine-grained sub-population identification. MLG is widely applicable to settings with single cell data integration via dimension reduction.

genomics↗

bioRxiv2021

GATA2 deficiency during embryogenesis elevates Interferon Regulatory Factor-8 to subvert a progenitor cell differentiation program

Cell type-specific transcription factors control stem and progenitor cell transitions by establishing networks containing hundreds of genes and proteins. Network complexity renders it challenging to discover essential versus modulatory or redundant components. This scenario is exemplified by GATA2 regulation of hematopoiesis during embryogenesis. Previously, we demonstrated that loss of Gata2, -77 enhancer disrupts the GATA2-dependent genetic network governing erythro-myeloid differentiation. The aberrant network includes the transcription factor Interferon Regulatory Factor-8 and a host of innate immune regulators. Mutant progenitors lose the capacity to balance production of diverse myelo-erythroid progeny. To elucidate mechanisms, we asked if IRF8 is essential, contributory or not required. Irf8 ablation, in the context of the -77 mutant allele, reversed granulocytic deficiencies of -77-/- embryos and rescued an imbalance of dendritic cell progenitors. Despite many dysregulated components that control vital processes, including transcription and signaling, aberrant elevation of a single transcription factor deconstructed the differentiation program.

developmental biology↗

bioRxiv2019

PRAM: a novel pooling approach for discovering intergenic transcripts from large-scale RNA sequencing experiments

Publicly available RNA-seq data is routinely used for retrospective analysis to elucidate new biology. Novel transcript discovery enabled by joint examination of large collections of RNA-seq datasets has emerged as one such analysis. Current methods for transcript discovery rely on a 2-Step approach where the first step encompasses building transcripts from individual datasets, followed by the second step that merges predicted transcripts across datasets. To increase the power of transcript discovery from large collections of RNA-seq datasets, we developed a novel 1-Step approach named Pooling RNA-seq and Assembling Models (PRAM) that builds transcript models from pooled RNA-seq datasets. We demonstrate in a computational benchmark that 1-Step outperforms 2-Step approaches in predicting overall transcript structures and individual splice junctions, while performing competitively in detecting exonic nucleotides. Applying PRAM to 30 human ENCODE RNA-seq datasets identified unannotated transcripts with epigenetic and RAMPAGE signatures similar to those of recently annotated transcripts. In a case study, we discovered and experimentally validated new transcripts through the application of PRAM to mouse hematopoietic RNA-seq datasets. Notably, we uncovered new transcripts that share a differential expression pattern with a neighboring gene Pik3cg implicated in human hematopoietic phenotypes, and we provided evidence for the conservation of this relationship in human. PRAM is implemented as an R/Bioconductor package and is available at https://bioconductor.org/packages/pram.

bioinformatics↗