FILER: a framework for harmonizing and querying large-scale functional genomics knowledge.

Querying massive functional genomic and annotation data collections, linking and summarizing the query results across data sources/data types are important steps in high-throughput genomic and genetic analytical workflows. However, these steps are made difficult by the heterogeneity and breadth of data sources, experimental assays, biological conditions/tissues/cell types and file formats. FILER (FunctIonaL gEnomics Repository) is a framework for querying large-scale genomics knowledge with a large, curated integrated catalog of harmonized functional genomic and annotation data coupled with a scalable genomic search and querying interface.

Using INFERNO to Infer the Molecular Mechanisms Underlying Noncoding Genetic Associations.

The INFERNO method provides an integrative computational framework for characterizing the causal variants, tissue contexts, affected regulatory mechanisms, and target genes underlying noncoding genetic variants associated with any phenotype or disease of interest. Here we describe the computational steps required to run the full INFERNO pipeline on any dataset of interest.

Author Correction: An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease.

Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac.

SparkINFERNO: a scalable high-throughput pipeline for inferring molecular mechanisms of non-coding genetic variants.

Summary: We report Spark-based INFERence of the molecular mechanisms of NOn-coding genetic variants (SparkINFERNO), a scalable bioinformatics pipeline characterizing non-coding genome-wide association study (GWAS) association findings. SparkINFERNO prioritizes causal variants underlying GWAS association signals and reports relevant regulatory elements, tissue contexts and plausible target genes they affect. To achieve this, the SparkINFERNO algorithm integrates GWAS summary statistics with large-scale collection of functional genomics datasets spanning enhancer activity, transcription factor binding, expression quantitative trait loci and other functional datasets across more than 400 tissues and cell types.

HIPPIE2: a method for fine-scale identification of physically interacting chromatin regions.

Most regulatory chromatin interactions are mediated by various transcription factors (TFs) and involve physically interacting elements such as enhancers, insulators or promoters. To map these elements and interactions at a fine scale, we developed HIPPIE2 that analyzes raw reads from high-throughput chromosome conformation (Hi-C) experiments to identify precise loci of DNA physically interacting regions (PIRs). Unlike standard genome binning approaches (e.

Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain.

Brain lesions composed of pathological tau help to drive neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Here, we identified the mammalian suppressor of tauopathy 2 () gene as a modifier of susceptibility to tau toxicity in two mouse models of tauopathy. Transgenic PS19 mice overexpressing tau, a model of AD, and lacking the gene exhibited decreased learning and memory deficits, reduced neurodegeneration, and reduced accumulation of pathological tau compared to PS19 tau transgenic mice expressing Conversely, overexpression in 4RTauTg2652 tau transgenic mice increased pathological tau deposition and promoted the neuroinflammatory response to pathological tau.

Inferring the Molecular Mechanisms of Noncoding Alzheimer's Disease-Associated Genetic Variants.

Most of the loci identified by genome-wide association studies (GWAS) for late-onset Alzheimer's disease (LOAD) are in strong linkage disequilibrium (LD) with nearby variants all of which could be the actual functional variants, often in non-protein-coding regions and implicating underlying gene regulatory mechanisms. We set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying these associations. We applied our INFERNO algorithm to the top 19 non-APOE loci from the IGAP GWAS study.

Loss of Nuclear TDP-43 Is Associated with Decondensation of LINE Retrotransposons.

Loss of the nuclear RNA binding protein TAR DNA binding protein-43 (TDP-43) into cytoplasmic aggregates is the strongest correlate to neurodegeneration in amyotrophic lateral sclerosis and frontotemporal degeneration. The molecular changes associated with the loss of nuclear TDP-43 in human tissues are not entirely known. Using subcellular fractionation and fluorescent-activated cell sorting to enrich for diseased neuronal nuclei without TDP-43 from post-mortem frontotemporal degeneration-amyotrophic lateral sclerosis (FTD-ALS) human brain, we characterized the effects of TDP-43 loss on the transcriptome and chromatin accessibility.

DASHR 2.0: integrated database of human small non-coding RNA genes and mature products.

Motivation: Small non-coding RNAs (sncRNAs, <100 nts) are highly abundant RNAs that regulate diverse and often tissue-specific cellular processes by associating with transcription factor complexes or binding to mRNAs. While thousands of sncRNA genes exist in the human genome, no single resource provides searchable, unified annotation, expression and processing information for full sncRNA transcripts and mature RNA products derived from these larger RNAs.

Results: Our goal is to establish a complete catalog of annotation, expression, processing, conservation, tissue-specificity and other biological features for all human sncRNA genes and mature products derived from all major RNA classes.

INFERNO: inferring the molecular mechanisms of noncoding genetic variants.

The majority of variants identified by genome-wide association studies (GWAS) reside in the noncoding genome, affecting regulatory elements including transcriptional enhancers. However, characterizing their effects requires the integration of GWAS results with context-specific regulatory activity and linkage disequilibrium annotations to identify causal variants underlying noncoding association signals and the regulatory elements, tissue contexts, and target genes they affect. We propose INFERNO, a novel method which integrates hundreds of functional genomics datasets spanning enhancer activity, transcription factor binding sites, and expression quantitative trait loci with GWAS summary statistics.

SPAR: small RNA-seq portal for analysis of sequencing experiments.

The introduction of new high-throughput small RNA sequencing protocols that generate large-scale genomics datasets along with increasing evidence of the significant regulatory roles of small non-coding RNAs (sncRNAs) have highlighted the urgent need for tools to analyze and interpret large amounts of small RNA sequencing data. However, it remains challenging to systematically and comprehensively discover and characterize sncRNA genes and specifically-processed sncRNA products from these datasets. To fill this gap, we present Small RNA-seq Portal for Analysis of sequencing expeRiments (SPAR), a user-friendly web server for interactive processing, analysis, annotation and visualization of small RNA sequencing data.

Publisher Correction: Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease.

In the version of this article initially published online, the fifth author's name was given as Alexander Amlie-Wolf. The correct name is Alexandre Amlie-Wolf. The error has been corrected in the print, PDF and HTML versions of this article.

Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease.

Aging is the strongest risk factor for Alzheimer's disease (AD), although the underlying mechanisms remain unclear. The chromatin state, in particular through the mark H4K16ac, has been implicated in aging and thus may play a pivotal role in age-associated neurodegeneration. Here we compare the genome-wide enrichment of H4K16ac in the lateral temporal lobe of AD individuals against both younger and elderly cognitively normal controls.

DASHR: database of small human noncoding RNAs.

Small non-coding RNAs (sncRNAs) are highly abundant RNAs, typically <100 nucleotides long, that act as key regulators of diverse cellular processes. Although thousands of sncRNA genes are known to exist in the human genome, no single database provides searchable, unified annotation, and expression information for full sncRNA transcripts and mature RNA products derived from these larger RNAs. Here, we present the Database of small human noncoding RNAs (DASHR).

Transcriptomic Changes Due to Cytoplasmic TDP-43 Expression Reveal Dysregulation of Histone Transcripts and Nuclear Chromatin.

TAR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking, and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm.