Biology subjects

Youn, A.

Publications and source records attributed to Youn, A..

4 recordsLinked to original sources

bioRxiv2022

Transcriptional activation of Jun and Fos members of the AP-1 complex is a conserved signature of immune aging that contributes to inflammaging

Diverse mouse strains have different health and life spans, mimicking the diversity among humans. To capture conserved aging signatures, we studied long-lived C57BL/6J and short-lived NZO/HILtJ mouse strains by profiling transcriptomes and epigenomes of immune cells from peripheral blood and the spleen from young and old mice. Transcriptional activation of the AP-1 transcription factor complex, particularly Fos, Junb, and Jun genes, was the most significant and conserved aging signature across tissues and strains. ATAC-seq data analyses showed that the chromatin around these genes was more accessible with age and there were significantly more binding sites for these TFs with age across all studied tissues, targeting pro-inflammatory molecules including Il6. Age-related increases in binding sites of Jun/Fos factors were also conserved in human peripheral blood ATAC-seq data. Single-cell RNA-seq data from the mouse aging cell atlas Tabula Muris Senis showed that the expression of these genes increased with age in B, T, NK cells, and macrophages, with macrophages from old mice expressing these molecules more abundantly than other cells. Functional data showed that upon myeloid cell activation via poly(I:C), the levels of c-JUN protein and its binding activity increased more significantly in spleen cells from old mice compared to cells from young mice. In addition, upon activation, old cells produced more IL6 compared to young cells. In sum, we showed that the aging-related transcriptional activation of Jun/Fos members of the AP-1 complex is conserved across immune tissues and long- and short-living mouse strains, possibly contributing to increased inflammation with age.

systems biology↗

bioRxiv2019

Calculating sample size for identifying cell subpopulation in single-cell RNA-seq experiments

SO_SCPLOWUMMARYC_SCPLOWSingle-cell RNA sequencing (scRNA-seq) is a rapidly developing technology for studying gene expression at the individual cell level and is often used to identify subpopulations of cells. Although the use of scRNA-seq is steadily increasing in basic and translational research, there is currently no statistical model for calculating the optimal number of cells for use in experiments that seek to identify cell subpopulations. Here, we have developed a statistical method ncells for calculating the number of cells required to detect a rare subpopulation in a homogeneous cell population for the given type I and II error. ncells defines power as the probability of separation of subpopulations which is calculated from three user-defined parameters: the proportion of rare subpopulation, proportion of up-regulated marker genes of the subpopulation, and levels of differential expression of the marker genes. We applied ncells to the scRNA-seq data on dendritic cells and monocytes isolated from healthy blood donor to show its efficacy in calculating the optimal number of cells in identifying a novel subpopulation.

bioinformatics↗

bioRxiv2018

BiFET: A Bias-free Transcription Factor Footprint Enrichment Test

Transcription factor (TF) footprinting uncovers putative protein-DNA binding via combined analyses of chromatin accessibility patterns and their underlying TF sequence motifs. TF footprints are frequently used to identify TFs that regulate activities of cell/condition-specific genomic regions (target loci) in comparison to control regions (background loci) using standard enrichment tests. However, there is a strong association between the chromatin accessibility level and the GC content of a locus and the number and types of TF footprints that can be detected at this site. Traditional enrichment tests (e.g., hypergeometric) do not account for this bias and inflate false positive associations. Therefore, we developed a novel method, Bias-free Footprint Enrichment Test (BiFET), that corrects for the biases arising from the differences in chromatin accessibility levels and GC contents between target and background loci in footprint enrichment analyses. We applied BiFET on TF footprint calls obtained from human EndoC-{beta}H1 ATAC-seq samples using three different algorithms (CENTIPEDE, HINT-BC, and PIQ) and showed BiFETs ability to increase power and reduce false positive rate when compared to hypergeometric test. Furthermore, we used BiFET to study TF footprints from human PBMC and pancreatic islet ATAC-seq samples to show its utility to identify putative TFs associated with cell-type-specific loci.

genomics↗

bioRxiv2017

Chromatin accessibility profiling uncovers genetic- and T2D disease state-associated changes in cis-regulatory element use in human islets

Genetic and environmental factors both contribute to islet dysfunction and failure, resulting in type 2 diabetes (T2D). The islet epigenome integrates these cues and can be remodeled by genetic and environmental variation. However, our knowledge of how genetic variants and T2D disease state alter human islet chromatin landscape and cis-regulatory element (RE) use is lacking. To fill this gap, we profiled and analyzed human islet chromatin accessibility maps from 19 genotyped individuals (5 with T2D) using ATAC-seq technology. Chromatin accessibility quantitative trait locus (caQTL) analyses identified 3001 sequence variants (FDR<10%) altering putative cis-RE use/activity. Islet caQTL were significantly and specifically enriched in islet stretch enhancers and islet-specific transcription factor binding motifs, such as FOXA2, NKX6.1, RFX5/6 and PDX1. Importantly, these analyses identified putative functional single nucleotide variants (SNVs) in 13 T2D-associated GWAS loci, including those previously associated with altered ZMIZ1, MTNR1B, RNF6, and ADCY5 islet expression, and linked the risk alleles to increased (n=8) or decreased (n=5) islet chromatin accessibility. Luciferase reporter assays confirmed allelic differences in cis-RE activity for 5/9 caQTL sequences tested, including a T2D-associated SNV in the IL20RA locus. Comparison of T2D and non-diabetic islets revealed 1882 open chromatin sites exhibiting T2D-associated chromatin accessibility changes (FDR<10%). Together, this study provides new insights into genetic variant and T2D disease state effects on islet cis-RE use and serves as an important resource to identify putative functional variants in T2D-and islet dysfunction-associated GWAS loci and link their risk allele to in vivo loss or gain of chromatin accessibility.

genomics↗