Cell genomics最新文献

Gene expression variation, an essential step between genotype and phenotype, is collectively controlled by local (cis) and distant (trans) regulatory changes. Nevertheless, how these regulatory elements differentially influence gene expression variation remains unclear. Here, we bridge this gap by analyzing the transcriptomes of a large diallel panel consisting of 323 unique hybrids originating from genetically divergent Saccharomyces cerevisiae isolates. Our analysis across 5,087 transcript abundance traits showed that non-additive components account for 36% of the gene expression variance on average. By comparing allele-specific read counts in parent-hybrid trios, we found that trans-regulatory changes underlie the majority of gene expression variation in the population. Remarkably, most cis-regulatory variations are also exaggerated or attenuated by additional trans effects. Overall, we showed that the transcriptome is globally buffered at the genetic level mainly due to trans-regulatory variation in the population.

In animal cells, molecular pathways often comprise families of variant components, such as ligands or receptors. These pathway components are differentially expressed by different cell types, potentially tailoring pathway function to cell context. However, it has remained unclear how pathway expression profiles are distributed across cell types and whether similar profiles can occur in dissimilar cell types. Here, using single-cell gene expression datasets, we identified pathway expression motifs, defined as recurrent expression profiles that are broadly distributed across diverse cell types. Motifs appeared in core pathways, including TGF-β, Notch, Wnt, and the SRSF splice factors, and involved combinatorial co-expression of multiple components. Motif usage was weakly correlated between pathways in adult cell types and during dynamic developmental transitions. Together, these results suggest a mosaic view of cell type organization, in which different cell types operate many of the same pathways in distinct modes.

PBRM1 is frequently mutated in cancers of epithelial origin. How PBRM1 regulates normal epithelial homeostasis, prior to cancer initiation, remains unclear. Here, we show that PBRM1's gene regulatory roles differ drastically between cell states, leveraging human skin epithelium (epidermis) as a research platform. In progenitors, PBRM1 predominantly functions to repress terminal differentiation to sustain progenitors' regenerative potential; in the differentiation state, however, PBRM1 switches toward an activator. Between these two cell states, PBRM1 retains its genomic binding but associates with differential interacting proteins. Our targeted screen identified the E3 SUMO ligase PIAS1 as a key interactor. PIAS1 co-localizes with PBRM1 on chromatin to directly repress differentiation genes in progenitors, and PIAS1's chromatin binding drastically diminishes in differentiation. Furthermore, SUMOylation contributes to PBRM1's repressive function in progenitor maintenance. Thus, our findings highlight PBRM1's cell-state-specific regulatory roles influenced by its protein interactome despite its stable chromatin binding.

Non-invasively evaluating gene expression products in human pre-implantation embryos remains a significant challenge. Here, we develop a non-invasive method for comprehensive characterization of the extracellular RNAs (exRNAs) in a single droplet of spent media that was used to culture human in vitro fertilization embryos. We generate the temporal extracellular transcriptome atlas (TETA) of human pre-implantation development. TETA consists of 245 exRNA sequencing datasets for five developmental stages. These data reveal approximately 4,000 exRNAs at each stage. The exRNAs of the developmentally arrested embryos are enriched with the genes involved in negative regulation of the cell cycle, revealing an exRNA signature of developmental arrest. Furthermore, a machine-learning model can approximate the morphology-based rating of embryo quality based on the exRNA levels. These data reveal the widespread presence of coding gene-derived exRNAs at every stage of human pre-implantation development, and these exRNAs provide rich information on the physiology of the embryo.

It is currently a challenge to perform noninvasive molecular biological analysis of in vitro fertilized embryos. In this issue of Cell Genomics, Wu et al.¹ developed a non-invasive method to evaluate human pre-implantation embryos by characterizing the extracellular RNAs in spent media from the culture of in vitro fertilization embryos.

Short tandem repeats (STRs) account for a substantial fraction of human genetic variation, but their contribution to complex human phenotypes is largely unknown. Margoliash et al. perform detailed genome-wide association analysis and fine-mapping of STRs in UK Biobank, identifying many STRs likely to influence variation in blood and serum traits.

The complement system is crucial for innate immunity and has been linked to autoimmune and psychiatric disorders. Borbye-Lorenzen et al.¹ perform GWASs and PheWASs of neonatal C3/C4 protein concentrations, finding multiple genome-wide significant loci, and identify sex-specific associations between C3 protein concentration and C4 copy number with risk for schizophrenia.

Short tandem repeats (STRs) are genomic regions consisting of repeated sequences of 1-6 bp in succession. Single-nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) do not fully capture STR effects. To study these effects, we imputed 445,720 STRs into genotype arrays from 408,153 White British UK Biobank participants and tested for association with 44 blood phenotypes. Using two fine-mapping methods, we identify 119 candidate causal STR-trait associations and estimate that STRs account for 5.2%-7.6% of causal variants identifiable from GWASs for these traits. These are among the strongest associations for multiple phenotypes, including a coding CTG repeat associated with apolipoprotein B levels, a promoter CGG repeat with platelet traits, and an intronic poly(A) repeat with mean platelet volume. Our study suggests that STRs make widespread contributions to complex traits, provides stringently selected candidate causal STRs, and demonstrates the need to consider a more complete view of genetic variation in GWASs.

Complement components have been linked to schizophrenia and autoimmune disorders. We examined the association between neonatal circulating C3 and C4 protein concentrations in 68,768 neonates and the risk of six mental disorders. We completed genome-wide association studies (GWASs) for C3 and C4 and applied the summary statistics in Mendelian randomization and phenome-wide association studies related to mental and autoimmune disorders. The GWASs for C3 and C4 protein concentrations identified 15 and 36 independent loci, respectively. We found no associations between neonatal C3 and C4 concentrations and mental disorders in the total sample (both sexes combined); however, post-hoc analyses found that a higher C3 concentration was associated with a reduced risk of schizophrenia in females. Mendelian randomization based on C4 summary statistics found an altered risk of five types of autoimmune disorders. Our study adds to our understanding of the associations between C3 and C4 concentrations and subsequent mental and autoimmune disorders.