Biology subjects

Beer, M. A.

Publications and source records attributed to Beer, M. A..

6 recordsLinked to original sources

bioRxiv2026

SARAF represses the mild hypothermia response through the regulation of JUN

The mild hypothermia response (MHR) is a conserved mammalian cytoprotective program activated upon exposure to mild hypothermia (32 degrees C) that contributes to the neuroprotective effects of therapeutic hypothermia following hypoxic injury. Although rapid changes in intracellular calcium occur upon cooling, the mechanisms linking calcium dynamics to the activation of core MHR factors such as SP1 and RBM3 remain incompletely defined. In this study, we used siRNA-mediated knockdown (KD) of candidate regulators in conjunction with novel mild hypothermia indicator (MHI) reporters to identify upstream modulators of MHR-associated transcription. We identify SARAF, a negative regulator of store-operated calcium entry (SOCE), as a repressor of both SP1 and RBM3 under normothermic conditions. SARAF depletion is associated with increased intracellular calcium release and enhanced SP1- and RBM3-linked transcriptional outputs. We identify JUN as an important downstream factor mediating SARAF depletion-dependent de-repression of the MHR and demonstrate that it undergoes activation rapidly upon cooling. Finally, SARAF depletion conferred significant cytoprotection against hypoxia-induced early apoptosis. Collectively, these findings establish SARAF as an upstream regulator of MHR-associated transcription and provide a functional link between cold-induced intracellular calcium dynamics and the induction of core MHR effectors.

molecular biology↗

bioRxiv2018

Local epigenomic state cannot discriminate interacting and non-interacting enhancer-promoter pairs with high accuracy

We report an overfitting issue in recent machine learning formulations of the enhancer-promoter interaction problem arising from the fact that many enhancer-promoter pairs share features. Cross- fold validation schemes which do not correctly separate these feature sharing enhancer-promoter pairs into one test set report high accuracy, which is actually due to overfitting. Cross-fold validation schemes which properly segregate pairs with shared features show markedly reduced ability to predict enhancer-promoter interactions from epigenomic state. Parameter scans with multiple models indicate that local epigenomic features of individual pairs of enhancers and promoters cannot distinguish those pairs that interact from those which do with high accuracy, suggesting that additional information is required to predict enhancer-promoter interactions.

genomics↗

bioRxiv2018

Parkinson-associated SNCA enhancer variants revealed by open chromatin in mouse dopamine neurons

The progressive loss of midbrain (MB) dopaminergic (DA) neurons defines the motor features of Parkinson disease (PD) and modulation of risk by common variation in PD has been well established through GWAS. Anticipating that a fraction of PD-associated genetic variation mediates their effects within this neuronal population, we acquired open chromatin signatures of purified embryonic mouse MB DA neurons. Correlation with >2,300 putative enhancers assayed in mice reveals enrichment for MB cis-regulatory elements (CRE), data reinforced by transgenic analyses of six additional sequences in zebrafish and mice. One CRE, within intron 4 of the familial PD gene SNCA, directs reporter expression in catecholaminergic neurons of transgenic mice and zebrafish. Sequencing of this CRE in 986 PD patients and 992 controls reveals two common variants associated with elevated PD risk. To assess potential mechanisms of action, we screened >20,000 DNA interacting proteins and identify a subset whose binding is impacted by these enhancer variants. Additional genotyping across the SNCA locus identifies a single PD-associated haplotype, containing the minor alleles of both of the aforementioned PD-risk variants. Our work posits a model for how common variation at SNCA may modulate PD risk and highlights the value of cell context-dependent guided searches for functional non-coding variation.

genetics↗

bioRxiv2018

Quantifying the unquantifiable: why Hymenoptera -- not Coleoptera -- is the most speciose animal order

BackgroundWe challenge the oft-repeated claim that the beetles (Coleoptera) are the most species-rich order of animals. Instead, we assert that another order of insects, the Hymenoptera, are more speciose, due in large part to the massively diverse but relatively poorly known parasitoid wasps. The idea that the beetles have more species than other orders is primarily based on their respective collection histories and the relative availability of taxonomic resources, which both disfavor parasitoid wasps. Though it is unreasonable to directly compare numbers of described species in each order, the ecology of parasitic wasps - specifically, their intimate interactions with their hosts - allows for estimation of relative richness. We present a simple logical model that shows how the specialization of many parasitic wasps on their hosts suggests few scenarios in which there would be more beetle species than parasitic wasp species. We couple this model with an accounting of what we call the \"genus-specific parasitoid-host ratio\" from four well-studied genera of insect hosts, a metric by which to generate extremely conservative estimates of the average number of parasitic wasp species attacking a given beetle or other insect host species. Synthesis of our model with data from real host systems suggests that the Hymenoptera may have 2.5 - 3.2x more species than the Coleoptera. While there are more described species of beetles than all other animals, the Hymenoptera are almost certainly the larger order.

zoology↗

bioRxiv2017

Embryonic loss of human females with partial trisomy 19 identifies region critical for the single active X

To compensate for the sex difference in the number of X chromosomes, human females, like human males have only one active X. The other X chromosomes in cells of both sexes are silenced in utero by XIST, the Inactive X Specific Transcript gene, that is present on all X chromosomes. To investigate the means by which the human active X is protected from silencing by XIST, we updated the search for a key dosage sensitive XIST repressor using new cytogenetic data with more precise resolution. Here, based on a previously unknown sex bias in copy number variations, we identify a unique region in our genome, and propose candidate genes that lie within, as they could inactivate XIST. Unlike males, the females who duplicate this region of chromosome 19 (partial 19 trisomy) do not survive embryogenesis; this preimplantation loss of females may be one reason that more human males are born than females.

genetics↗

bioRxiv2016

Genetic determinants of chromatin accessibility and gene regulation in T cell activation across human individuals

Over 90% of genetic variants associated with complex human traits map to non-coding regions, but little is understood about how they modulate gene regulation in health and disease. One possible mechanism is that genetic variants affect the activity of one or more cis-regulatory elements leading to gene expression variation in specific cell types. To identify such cases, we analyzed Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) and RNA-seq profiles from activated CD4+ T cells of up to 105 healthy donors. We found that regions of accessible chromatin (ATAC-peaks) are co-accessible at kilobase and megabase resolution, in patterns consistent with the 3D organization of chromosomes measured by in situ Hi-C in T cells. 15% of genetic variants located within ATAC-peaks affected the accessibility of the corresponding peak through disrupting binding sites for transcription factors important for T cell differentiation and activation. These ATAC quantitative trait nucleotides (ATAC-QTNs) have the largest effects on co-accessible peaks, are associated with gene expression from the same aliquot of cells, are rarely affecting core binding motifs, and are enriched for autoimmune disease variants. Our results provide insights into how natural genetic variants modulate cis- regulatory elements, in isolation or in concert, to influence gene expression in primary immune cells that play a key role in many human diseases.

genomics↗