Biology subjects

Boehm, K.

Publications and source records attributed to Boehm, K..

7 recordsLinked to original sources

bioRxiv2025

Short Polysialic Acid Counteracts Age-Related Synaptic and Cognitive Deficits

Impaired activity of glutamate transporters, elevated concentration of extrasynaptic glutamate and hyperactivity of extrasynaptic GluN2B-containing NMDA receptors are common features in aging and several neurological conditions, including Alzheimers disease (AD). Previous studies revealed that polysialic acid (polySia), a glycan predominantly carried by the neural cell adhesion molecule NCAM, inhibits extrasynaptic NMDA receptors and supports synaptic plasticity in healthy adult brains. Moreover, intranasal delivery of polySia with the degree of polymerization 12 (NANA12) rescued synaptic plasticity and cognitive functions in models of tauopathy and amyloidosis associated with AD. Here, we comparatively studied the effects of NANA12 in young (4 months) old (26 months) and very old (29 months) mice. Strikingly, NANA12 promoted cognitive flexibility in attentional set-shifting (ASST) tests and spatial memory in the Barnes maze in very old mice. To capture fine-grained effects undetectable by conventional methods, we introduced a novel trial-wise data analysis approach for evaluating ASST performance. The observed cognitive improvements were not due to changes in the size of hippocampal memory engrams, visualized by c-Fos immunolabeling after reactivation of spatial memory in the probe trial. Five-day treatment with NANA12 did not affect neuronal structure (MAP2 levels), expression of senescence (lipofuscin) or neuroinflammation (microglial Iba1) markers, activation of BDNF receptors (p-TrkB) or expression of endogenous polySia in the hippocampus of very old mice. However, cognitive improvements correlated with the normalized size of CD68+ microglial lysosomes and reduced amounts of pre- and postsynaptic proteins at these structures. Thus, our data demonstrate the potential of short polySia to reduce synaptic phagocytosis and restore key cognitive functions attenuated in aging.

neuroscience↗

bioRxiv2024

Exploring the Efficiency of Deep Graph Neural Networks for RNA Secondary Structure Prediction

Ribonucleic acid (RNA) plays a vital role in various biological processes and forms intricate secondary and tertiary structures associated with its functions. Predicting RNA secondary structures is essential for understanding the functional and regulatory roles of RNA molecules in biological processes. Traditional free-energy-based methods for predicting these structures often fail to capture complex interactions and long-range dependencies within RNA sequences. Recent advancements in machine learning, particularly with graph neural networks (GNNs), have shown promise in enhancing the ability to model the relationships between molecular sequences and their structures. This work specifically explores the efficacy of various GNN architectures in modeling RNA secondary structure. Through benchmarking the GNN methods against traditional energy-based models on standard datasets, our analysis demonstrates that GNN models improves traditional methods, offering a robust framework for accurate RNA structure prediction.

bioinformatics↗

bioRxiv2023

Variant-to-function analysis of the childhood obesity chr12q13 locus implicates rs7132908 as a causal variant within the 3' UTR of FAIM2

The ch12q13 obesity locus is among the most significant childhood obesity loci identified in genome-wide association studies. This locus resides in a non-coding region within FAIM2; thus, the underlying causal variant(s) presumably influence disease susceptibility via an influence on cis-regulation within the genomic region. We implicated rs7132908 as a putative causal variant at this locus leveraging a combination of our inhouse 3D genomic data, public domain datasets, and several computational approaches. Using a luciferase reporter assay in human primary astrocytes, we observed allele-specific cis-regulatory activity of the immediate region harboring rs7132908. Motivated by this finding, we went on to generate isogenic human embryonic stem cell lines homozygous for either rs7132908 allele with CRISPR-Cas9 homology-directed repair to assess changes in gene expression due to genotype and chromatin accessibility throughout a differentiation to hypothalamic neurons, a key cell type known to regulate feeding behavior. We observed that the rs7132908 obesity risk allele influenced the expression of FAIM2 along with other genes, decreased the proportion of neurons produced during differentiation, up-regulated cell death gene sets, and conversely down-regulated neuron differentiation gene sets. We have therefore functionally validated rs7132908 as a causal obesity variant which temporally regulates nearby effector genes at the ch12q13 locus and influences neurodevelopment and survival.

genetics↗

bioRxiv2021

The three-dimensional chromatin structure of the major human pancreatic cell types reveals lineage-specific regulatory architecture of T2D risk

Three-dimensional (3D) chromatin organization maps help to dissect cell type-specific gene regulatory programs. Furthermore, 3D chromatin maps have contributed to elucidating the pathogenesis of complex genetic diseases by connecting distal regulatory regions and genetic risk variants to their respective target genes. To understand the cell type-specific regulatory architecture of diabetes risk, we generated transcriptomic and 3D epigenomic profiles of human pancreatic acinar, alpha, and beta cells using single-cell RNA-seq, single-cell ATAC-seq, and high-resolution Hi-C of sorted cells. Comparisons of these profiles revealed differential A/B (open/closed) chromatin compartmentalization, chromatin looping, and transcriptional factor mediated control of cell type-specific gene regulatory programs. We identified a total of 4,750 putative causal-variant-target-gene pairs at 194 type 2 diabetes GWAS signals using pancreatic 3D chromatin maps. We found that the connections between candidate causal variants and their putative target effector genes are cell-type stratified and emphasize previously underappreciated roles for alpha and acinar cells in diabetes pathogenesis.

genetics↗

bioRxiv2020

Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant common complex traits

SummaryThe hypothalamus regulates metabolic homeostasis by influencing behavior, energy utilization and endocrine systems. Given its role governing health-relevant traits, such as body weight and reproductive timing, understanding the genetic regulation of hypothalamic development and function should yield insights into these traits and diseases. However, given its inaccessibility, studying human hypothalamic gene regulation has proven challenging. To address this gap, we generated a chromatin architecture atlas of an established embryonic stem cell (ESC)-derived hypothalamic-like neuron (HN) model across three stages of in vitro differentiation. We profiled accessible chromatin and identified physically interacting contacts between gene promoters and their putative cis-regulatory elements (cREs) to characterize changes in the gene regulatory landscape during hypothalamic differentiation. Next, we integrated these data with GWAS loci for multiple traits and diseases enriched for heritability in these cells, identifying candidate effector genes and cREs impacting transcription factor binding. Our results reveal common target genes for these traits, potentially identifying core hypothalamic developmental pathways. Our atlas will enable future efforts to determine precise mechanisms underlying hypothalamic development with respect to specific disease pathogenesis.Competing Interest StatementThe authors have declared no competing interest.View Full Text

genomics↗

bioRxiv2019

Chromosome organization by a conserved condensin-ParB system in the actinobacterium Corynebacterium glutamicum

Higher-order chromosome folding and segregation is tightly regulated in all domains of life. In bacteria, details on nucleoid organization regulatory mechanisms and function remains poorly characterized, especially in non-model species. Here, we investigate the role of DNA partitioning protein ParB and condensin complexes, two key players in bacterial chromosome structuring, in the actinobacterium Corynebacterium glutamicum. Chromosome conformation capture reveals SMC-mediated long-range interactions around ten centromere-like parS sites clustered at the replication origin (oriC). At least one oriC-proximal parS site is necessary for a reliable chromosome segregation. Using a combination of chromatin immunoprecipitation and photoactivated single molecule localization microscopy evidences the formation of distinct ParB-nucleoprotein subclusters in dependence of parS numbers. We further identified and functionally characterized two condensin paralogs. Whereas SMC/ScpAB complexes are loaded via ParB at parS sites mediating chromosomal inter-arm contacts like in Bacillus subtilis, the MukBEF-like SMC complex MksBEFG does not contribute to chromosomal DNA-folding. Rather, the MksBEFG complex is involved in plasmid maintenance and interacts with the polar oriC-tethering factor DivIVA. These data complement current models of ParB-SMC/ScpAB crosstalk, while showing that some condensin complexes evolved functions uncoupled from chromosome folding.

microbiology↗

bioRxiv2016

Novel chromosome organization pattern in actinomycetales-overlapping replication cycles combined with diploidy

Bacteria regulate chromosome replication and segregation tightly with cell division to ensure faithful segregation of DNA to daughter generations. The underlying mechanisms have been addressed in several model species. It became apparent that bacteria have evolved quite different strategies to regulate DNA segregation and chromosomal organization. We have investigated here how the actinobacterium Corynebacterium glutamicum organizes chromosome segregation and DNA replication. Unexpectedly, we find that C. glutamicum cells are at least diploid under all conditions tested and that these organisms have overlapping C-periods during replication with both origins initiating replication simultaneously. Based on experimentally obtained data we propose growth rate dependent cell cycle models for C. glutamicum.

microbiology↗