Biology subjects

Erikson, G.

Publications and source records attributed to Erikson, G..

4 recordsLinked to original sources

bioRxiv2021

Discovering single nucleotide variants and indels from bulk and single-cell ATAC-seq

Genetic variants and de novo mutations in regulatory regions of the genome are typically discovered by whole-genome sequencing (WGS), however WGS is expensive and most WGS reads come from non-regulatory regions. The Assay for Transposase-Accessible Chromatin (ATAC-seq) generates reads from regulatory sequences and could potentially be used as a low-cost capture method for regulatory variant discovery, but its use for this purpose has not been systematically evaluated. Here we apply seven variant callers to bulk and single-cell ATAC-seq data and evaluate their ability to identify single nucleotide variants (SNVs) and insertions/deletions (indels). In addition, we develop an ensemble classifier, VarCA, which combines features from individual variant callers to predict variants. The Genome Analysis Toolkit (GATK) is the best-performing individual caller with precision/recall on a bulk ATAC test dataset of 0.92/0.97 for SNVs and 0.87/0.82 for indels. On bulk ATAC-seq reads, VarCA achieves superior performance with precision/recall of 0.99/0.95 for SNVs and 0.93/0.80 for indels. On single-cell ATAC-seq reads, VarCA attains precision/recall of 0.98/0.94 for SNVs and 0.82/0.82 for indels. In summary, ATAC-seq reads can be used to accurately discover non-coding regulatory variants in the absence of whole-genome sequencing data and our ensemble method, VarCA, has the best overall performance.

bioinformatics↗

bioRxiv2019

Tuft cells restrain pancreatic tumorigenesis through paracrine eicosanoid signaling

Despite numerous advances in our understanding of pancreatic ductal adenocarcinoma (PDA) genetics and biology, this disease is expected to become the second leading cause of cancer-related U.S. deaths within the next few years. Incomplete understanding of how it arises precludes development of early detection and interception strategies to improve therapeutic outcomes. Acinar to ductal metaplasia involving genesis of tuft cells is one early step in PDA formation, but their functional significance has remained obscure due to their rarity and a lack of methods and relevant animal models for their molecular and functional analysis. Here, we show that deletion of tuft cell master regulator Pou2f3 eliminates pancreatic tuft cells and increases fibrosis, alters immune cell activation, and accelerates disease progression. We demonstrate that tuft cell expression of the prostaglandin D2 synthase Hpgds restrains pancreatic disease progression in early stages by inhibiting stromal activation. Analyses of human data sets are consistent with mouse studies. We propose that tuft cells and, by inference, the associated metaplastic lesions, play a protective role early in pancreatic tumorigenesis. SignificanceWe find that tuft cell formation in response to oncogenic Kras is protective and restrains tumorigenesis through local production of anti-inflammatory substances, including paracrine prostaglandin D2 signaling to the stroma. Our findings establish tuft cells as a metaplasia-induced tumor suppressive cell type.

cancer biology↗

bioRxiv2019

Aging of human endocrine pancreatic cell types is heterogeneous and sex-specific

The human endocrine pancreas must regulate glucose homeostasis throughout the human lifespan, which is generally decades. We performed meta-analysis of single-cell, RNA-sequencing datasets derived from 36 individuals, as well as functional analyses, to characterize age-associated changes to the major endocrine pancreatic cell types. Increasing age was associated with shifts in pancreatic alpha and beta cell identity and loss of nuclear integrity in non-diabetic humans. In non-diabetic individuals [≥] 50 years old, 80% of their beta cells exhibited a transcriptional signature similar to cells from type-2 diabetic (T2D) donors. Surprisingly, [~]5% of beta cells from T2D donors retained a youthful, N.D. transcriptional profile. Furthermore, beta cell function was reduced by 50% during aging in men but not women, which may explain sex-associated differences in diabetes etiology. These analyses reveal that aging of the human endocrine pancreas is sex- and cell-type specific.

physiology↗

bioRxiv2019

BreakCA, a method to discover indels using ChIP-seq and ATAC-seq reads, finds recurrent indels in regulatory regions of neuroblastoma genomes

Most known cancer driver mutations are within protein coding regions of the genome, however, there are several important examples of oncogenic non-coding regulatory mutations. We developed a method to identify insertions and deletions (indels) in regulatory regions using aligned reads from chromatin immunoprecipitation followed by sequencing (ChIP-seq) or the assay for transposase-accessible chromatin (ATAC-seq). Our method, which we call BreakCA for Breaks in Chromatin Accessible regions, allows non-coding indels to be discovered in the absence of whole genome sequencing data, out-performs popular variant callers such as the GATK-HaplotypeCaller and VarScan2, and detects known oncogenic regulatory mutations in T-cell acute lymphoblastic leukemia cell lines. We apply BreakCA to identify indels in H3K27ac ChIP-seq peaks in 23 neuroblastoma cell lines and, after removing common germline variants, we identify 23 rare germline or somatic indels that occur in multiple neuroblastoma cell lines. Among them, 4 indels are candidate oncogenic drivers that are present in 4 or 5 cell lines, absent from the genome aggregation database of over 15,000 whole genome sequences, and within the promoters or first introns of known genes (PHF21A, ADAMTS19, GPR85 and RALGDS). In addition, we observe a rare 7bp germline deletion in two cell lines, which is associated with high expression of the histone demethylase KDM5B. Overexpression of KDM5B is prognostic for many cancers and further characterization of this indel as a potential oncogenic risk factor is therefore warranted.

bioinformatics↗