PaxDb 5.0: Curated Protein Quantification Data Suggests Adaptive Proteome Changes in Yeasts.

The "Protein Abundances Across Organisms" database (PaxDb) is an integrative metaresource dedicated to protein abundance levels, in tissue-specific or whole-organism proteomes. PaxDb focuses on computing best-estimate abundances for proteins in normal/healthy contexts and expresses abundance values for each protein in "parts per million" in relation to all other protein molecules in the cell. The uniform data reprocessing, quality scoring, and integrated orthology relations have made PaxDb one of the preferred tools for comparisons between individual datasets, tissues, or organisms. In describing the latest version 5.0 of PaxDb, we particularly emphasize the data integration from various types of raw data and how we expanded the number of organisms and tissue groups as well as the proteome coverage. The current collection of PaxDb includes 831 original datasets from 170 species, including 22 Archaea, 81 Bacteria, and 67 Eukaryota. Apart from detailing the data update, we also present a comparative analysis of the human proteome subset of PaxDb against the two most widely used human proteome data resources: Human Protein Atlas and Genotype-Tissue Expression. Lastly, through our protein abundance data, we reveal an evolutionary trend in the usage of sulfur-containing amino acids in the proteomes of Fungi.

Identifying gene function and module connections by the integration of multispecies expression compendia.

The functions of many eukaryotic genes are still poorly understood. Here, we developed and validated a new method, termed GeneBridge, which is based on two linked approaches to impute gene function and bridge genes with biological processes. First, Gene-Module Association Determination (G-MAD) allows the annotation of gene function. Second, Module-Module Association Determination (M-MAD) allows predicting connectivity among modules. We applied the GeneBridge tools to large-scale multispecies expression compendia-1700 data sets with over 300,000 samples from human, mouse, rat, fly, worm, and yeast-collected in this study. G-MAD identifies novel functions of genes-for example, DDT in mitochondrial respiration and WDFY4 in T cell activation-and also suggests novel components for modules, such as for cholesterol biosynthesis. By applying G-MAD on data sets from respective tissues, tissue-specific functions of genes were identified-for instance, the roles of EHHADH in liver and kidney, as well as SLC6A1 in brain and liver. Using M-MAD, we identified a list of module-module associations, such as those between mitochondria and proteasome, mitochondria and histone demethylation, as well as ribosomes and lipid biosynthesis. The GeneBridge tools together with the expression compendia are available as an open resource, which will facilitate the identification of connections linking genes, modules, phenotypes, and diseases.

Candidate targets of copy number deletion events across 17 cancer types.

Genome variation is the direct cause of cancer and driver of its clonal evolution. While the impact of many point mutations can be evaluated through their modification of individual genomic elements, even a single copy number aberration (CNA) may encompass hundreds of genes and therefore pose challenges to untangle potentially complex functional effects. However, consistent, recurring and disease-specific patterns in the genome-wide CNA landscape imply that particular CNA may promote cancer-type-specific characteristics. Discerning essential cancer-promoting alterations from the inherent co-dependency in CNA would improve the understanding of mechanisms of CNA and provide new insights into cancer biology and potential therapeutic targets. Here we implement a model using segmental breakpoints to discover non-random gene coverage by copy number deletion (CND). With a diverse set of cancer types from multiple resources, this model identified common and cancer-type-specific oncogenes and tumor suppressor genes as well as cancer-promoting functional pathways. Confirmed by differential expression analysis of data from corresponding cancer types, the results show that for most cancer types, despite dissimilarity of their CND landscapes, similar canonical pathways are affected. In 25 analyses of 17 cancer types, we have identified 19 to 169 significant genes by copy deletion, including RB1, PTEN and CDKN2A as the most significantly deleted genes among all cancer types. We have also shown a shared dependence on core pathways for cancer progression in different cancers as well as cancer type separation by genome-wide significance scores. While this work provides a reference for gene specific significance in many cancers, it chiefly contributes a general framework to derive genome-wide significance and molecular insights in CND profiles with a potential for the analysis of rare cancer types as well as non-coding regions.

Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis.

Bile acids (BAs) are complex and incompletely understood enterohepatic-derived hormones that control whole-body metabolism. Here, we profiled postprandial BAs in the liver, feces, and plasma of 360 chow- or high-fat-diet-fed BXD male mice and demonstrated that both genetics and diet strongly influence BA abundance, composition, and correlation with metabolic traits. Through an integrated systems approach, we mapped hundreds of quantitative trait loci that modulate BAs and identified both known and unknown regulators of BA homeostasis. In particular, we discovered carboxylesterase 1c (Ces1c) as a genetic determinant of plasma tauroursodeoxycholic acid (TUDCA), a BA species with established disease-preventing actions. The association between Ces1c and plasma TUDCA was validated using data from independent mouse cohorts and a Ces1c knockout mouse model. Collectively, our data are a unique resource to dissect the physiological importance of BAs as determinants of metabolic traits, as underscored by the identification of CES1C as a master regulator of plasma TUDCA levels.

The Progenetix oncogenomic resource in 2021.

In cancer, copy number aberrations (CNAs) represent a type of nearly ubiquitous and frequently extensive structural genome variations. To disentangle the molecular mechanisms underlying tumorigenesis as well as identify and characterize molecular subtypes, the comparative and meta-analysis of large genomic variant collections can be of immense importance. Over the last decades, cancer genomic profiling projects have resulted in a large amount of somatic genome variation profiles, however segregated in a multitude of individual studies and datasets. The Progenetix project, initiated in 2001, curates individual cancer CNA profiles and associated metadata from published oncogenomic studies and data repositories with the aim to empower integrative analyses spanning all different cancer biologies. During the last few years, the fields of genomics and cancer research have seen significant advancement in terms of molecular genetics technology, disease concepts, data standard harmonization as well as data availability, in an increasingly structured and systematic manner. For the Progenetix resource, continuous data integration, curation and maintenance have resulted in the most comprehensive representation of cancer genome CNA profiling data with 138 663 (including 115 357 tumor) copy number variation (CNV) profiles. In this article, we report a 4.5-fold increase in sample number since 2013, improvements in data quality, ontology representation with a CNV landscape summary over 51 distinctive National Cancer Institute Thesaurus cancer terms as well as updates in database schemas, and data access including new web front-end and programmatic data access. Database URL: progenetix.org.

Central anorexigenic actions of bile acids are mediated by TGR5.

Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain1, yet their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs2 and an established regulator of peripheral metabolism3-8. Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho-ROCK-actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system.

Enabling population assignment from cancer genomes with SNP2pop.

In many cancers, incidence, treatment efficacy and overall prognosis vary between geographic populations. Studies disentangling the contributing factors may help in both understanding cancer biology and tailoring therapeutic interventions. Ancestry estimation in such studies should preferably be driven by genomic data, due to frequently missing or erroneous self-reported or inferred metadata. While respective algorithms have been demonstrated for baseline genomes, such a strategy has not been shown for cancer genomes carrying a substantial somatic mutation load. We have developed a bioinformatics tool for the assignment of population groups from genome profiling data for both unaltered and cancer genomes. Despite extensive somatic mutations in the cancer genomes, consistency between germline and cancer data reached of 97% and 92% for assignment into 5 and 26 ancestral groups, respectively. Comparison with self-reported meta-data estimated a matching rate between 88-92%, mostly limited by interpretation of self-reported ethnicity labels compared to the standardized mapping output. Our SNP2pop application allows to assess population information from SNP arrays as well as sequencing platforms and to estimate the population structure in cancer genomics projects, to facilitate research into the interplay between ethnicity-related genetic background, environmental factors and somatic mutation patterns in cancer biology.

The Ubiquitin Ligase TRIP12 Limits PARP1 Trapping and Constrains PARP Inhibitor Efficiency.

PARP inhibitors (PARPi) cause synthetic lethality in BRCA-deficient tumors. Whether specific vulnerabilities to PARPi exist beyond BRCA mutations and related defects in homology-directed repair (HDR) is not well understood. Here, we identify the ubiquitin E3 ligase TRIP12 as negative regulator of PARPi sensitivity. We show that TRIP12 controls steady-state PARP1 levels and limits PARPi-induced cytotoxic PARP1 trapping. Upon loss of TRIP12, elevated PARPi-induced PARP1 trapping causes increased DNA replication stress, DNA damage, cell cycle arrest, and cell death. Mechanistically, we demonstrate that TRIP12 binds PARP1 via a central PAR-binding WWE domain and, using its carboxy-terminal HECT domain, catalyzes polyubiquitylation of PARP1, triggering proteasomal degradation and preventing supra-physiological PARP1 accumulation. Further, in cohorts of breast and ovarian cancer patients, PARP1 abundance is negatively correlated with TRIP12 expression. We thus propose TRIP12 as regulator of PARP1 stability and PARPi-induced PARP trapping, with potential implications for PARPi sensitivity and resistance.

Geographic assessment of cancer genome profiling studies.

Cancers arise from the accumulation of somatic genome mutations, which can be influenced by inherited genomic variants and external factors such as environmental or lifestyle-related exposure. Due to the heterogeneity of cancers, precise information about the genomic composition of germline and malignant tissues has to be correlated with morphological, clinical and extrinsic features to advance medical knowledge and treatment options. With global differences in cancer frequencies and disease types, geographic data is of importance to understand the interplay between genetic ancestry and environmental influence in cancer incidence, progression and treatment outcome. In this study, we analyzed the current landscape of oncogenomic screening publications for geographic information content and quality, to address underrepresented study populations and thereby to fill prominent gaps in our understanding of interactions between somatic variations, population genetics and environmental factors in oncogenesis. We conclude that while the use of proxy-derived geographic annotations can be useful for coarse-grained associations, the study of geo-correlated factors in cancer causation and progression will benefit from standardized geographic provenance annotations. Additionally, publication-derived geographic provenance data allowed us to highlight stark inequality in the geographies of cancer genome profiling, with a near lack of sizable studies from Africa and other large regions.

IGFBP2 Plays an Essential Role in Cognitive Development during Early Life.

Identifying the mechanisms underlying cognitive development in early life is a critical objective. The expression of insulin-like growth factor binding protein 2 (IGFBP2) in the hippocampus increases during neonatal development and is associated with learning and memory, but a causal connection has not been established. Here, it is reported that neurons and astrocytes expressing IGFBP2 are distributed throughout the hippocampus. IGFBP2 enhances excitatory inputs onto CA1 pyramidal neurons, facilitating intrinsic excitability and spike transmission, and regulates plasticity at excitatory synapses in a cell-type specific manner. It facilitates long-term potentiation (LTP) by enhancing N-methyl-d-aspartate (NMDA) receptor-dependent excitatory postsynaptic current (EPSC), and enhances neurite proliferation and elongation. Knockout of igfbp2 reduces the numbers of pyramidal cells and interneurons, impairs LTP and cognitive performance, and reduces tonic excitation of pyramidal neurons that are all rescued by IGFBP2. The results provide insight into the requirement for IGFBP2 in cognition in early life.

segment_liftover : a Python tool to convert segments between genome assemblies.

The process of assembling a species' reference genome may be performed in a number of iterations, with subsequent genome assemblies differing in the coordinates of mapped elements. The conversion of genome coordinates between different assemblies is required for many integrative and comparative studies. While currently a number of bioinformatics tools are available to accomplish this task, most of them are tailored towards the conversion of single genome coordinates. When converting the boundary positions of segments spanning larger genome regions, segments may be mapped into smaller sub-segments if the original segment's continuity is disrupted in the target assembly. Such a conversion may lead to a relevant degree of data loss in some circumstances such as copy number variation (CNV) analysis, where the quantitative representation of a genomic region takes precedence over base-specific accuracy. segment_liftover aims at continuity-preserving remapping of genome segments between assemblies and provides features such as approximate locus conversion, automated batch processing and comprehensive logging to facilitate processing of datasets containing large numbers of structural genome variation data.

An Integrated Systems Genetics and Omics Toolkit to Probe Gene Function.

Identifying genetic and environmental factors that impact complex traits and common diseases is a high biomedical priority. Here, we developed, validated, and implemented a series of multi-layered systems approaches, including (expression-based) phenome-wide association, transcriptome-/proteome-wide association, and (reverse-) mediation analysis, in an open-access web server (systems-genetics.org) to expedite the systems dissection of gene function. We applied these approaches to multi-omics datasets from the BXD mouse genetic reference population, and identified and validated associations between genes and clinical and molecular phenotypes, including previously unreported links between Rpl26 and body weight, and Cpt1a and lipid metabolism. Furthermore, through mediation and reverse-mediation analysis we established regulatory relations between genes, such as the co-regulation of BCKDHA and BCKDHB protein levels, and identified targets of transcription factors E2F6, ZFP277, and ZKSCAN1. Our multifaceted toolkit enabled the identification of gene-gene and gene-phenotype links that are robust and that translate well across populations and species, and can be universally applied to any populations with multi-omics datasets.

Activation of D1-like dopamine receptors increases the NMDA-induced gain modulation through a PKA-dependent pathway in the premotor nucleus of adult zebra finches.

Interaction between dopamine (DA) and N-methyl-d-aspartate (NMDA) in the brain plays an important role in learning and memory. In the songbirds, the premotor robust nucleus of the arcopallium (RA) receives excitatory glutamatergic inputs from the high vocal center (HVC) and lateral magnocellular nucleus of the anterior nidopallium (LMAN), as well as dopaminergic inputs mostly from the periaqueductal gray (PAG) and ventral tegmental area (VTA). In zebra finch, DA potentiates the excitability of projection neurons in the RA through activation of D1-like dopamine receptors (D1 receptors). The relationship between D1 receptors and NMDA in the RA projection neurons is essentially unknown. Our previous work showed that NMDA can induce gain modulation in the RA projection neurons. Here, using the whole-cell current-clamp recording from brain slices of male zebra finches, we observed whether D1 receptors regulate the NMDA-induced gain modulation in the RA projection neurons. Our results showed that activation of D1 receptors further increased the slope (gain) of the firing frequency-injected current (f-I) relationship induced by NMDA in the RA projection neurons. Blocking D1 receptors had no effect on the NMDA-induced gain modulation in the RA projection neurons. The enhanced effects of D1 receptors agonists were blocked by protein kinase A (PKA) inhibitors. Our results suggest that activation of D1 receptors can increase the NMDA-induced gain modulation through a PKA-dependent pathway.

Sex differences of excitatory synaptic transmission in RA projection neurons of adult zebra finches.

Zebra finches are ideal animals to investigate sex difference in songbirds. Only males can sing. The brain nuclei controlling song learning and production in males are considerably larger than in females. The robust nucleus of the arcopallium (RA) is a premotor nucleus, playing a key role in controlling singing. RA receives denser synapse inputs in males than in females. Sex differences of excitatory synaptic transmission in the RA projection neurons (PNs) have not been reported. In the present study, using whole-cell voltage-clamp recording, spontaneous EPSCs (sEPSCs) and miniature EPSCs (mEPSCs) of RA PNs in the intact males and females were recorded. The average frequency and amplitude of sEPSCs/mEPSCs in the intact males were higher than females. The half-width and decay time of sEPSCs/mEPSCs in the intact males were longer than females. In order to verify whether these sex differences related to sex steroids, males were castrated. The average frequency of sEPSCs/mEPSCs in castrated males was lower than intact males and was similar to in females; the amplitude was not changed after castrating. These results demonstrate the sexually dimorphic of the excitatory synaptic transmission in the RA PNs, the RA PNs in males receive more excitatory synaptic transmission and these sex differences were partly affected by sex hormones. These findings contribute to further illuminate the neural mechanisms under the sexually dimorphism in song production of adult zebra finches.