Biology subjects

Tegner, J. N.

Publications and source records attributed to Tegner, J. N..

4 recordsLinked to original sources

bioRxiv2026

Co-regulatory changes in Homo sapiens prefrontal cortex shape RNA-chromatin interactions

Noncoding RNAs (ncRNAs) regulate gene expression through RNA-chromatin interactions, yet their role in human brain evolution remains unclear. To map these interactions, we integrated FANTOM6 neurogenic data with a comprehensive atlas of regulatory regions active during early cortical development. This integration effort linked ncRNAs and transcription factors (TFs) to their genomic targets, revealing functional interactions captured by RNA-DNA contact mapping, yet largely missed by chromatin conformation data. Overlaying these interactions with nearly fixed variants in Homo sapiens relative to extinct hominins uncovered widespread rewiring of TF binding, affecting genes implicated in progenitor proliferation and neuronal differentiation. Gene regulatory network reconstruction identified TEAD2 and ONECUT2 as key regulators of intermediate progenitors and migrating neurons. Functional perturbation followed by Cut&Tag and ATAC-seq linked the two TFs to disease- and evolutionarily- relevant pathways. Together, these results show how ncRNA-TF cooperation and selective cis-regulatory rewiring contributed to sapiens-specific features of cortical development.

molecular biology↗

bioRxiv2025

Human growth plates house resting zone sub-populations with features of quiescent stem cells

Incomplete mapping of gene expression within human (epiphyseal) growth plates contributes to the challenges of diagnosing and treating patients with skeletal growth disorders. To address this issue, we applied spatially resolved transcriptomics to rare growth plate biopsies obtained from healthy adolescents. In addition to identifying novel markers of each zone of the human growth plate, spatial profiling revealed that the expression of genes associated with poorly understood growth disorders, including NKX3-2, SGMS2 and WNK4, is restricted to specific human growth plate zones. By elaborating on the low transcriptional activity of resting zone chondrocytes, we found that a subset of these cells exists in a functionally quiescent state in vivo, as determined by their predominantly nuclear mRNA, abundant heterochromatin, and ability to exit the G0 phase under specific conditions - features shared with skeletal stem cells in mouse growth plates. Additionally, we identified distinct and overlapping sub-populations of human resting zone chondrocytes; an exploration of their hierarchy determined that CHRDL2 and/or SFRP5-positive sub-populations are among the least quiescent resting zone cells. In summary, we generated the most comprehensive gene expression characterization of the human growth plate, which revealed novel zone-specific markers, new primary growth disorders, candidate pharmacological targets, and led us to uncover sub-populations of resting zone chondrocytes with features of quiescent stem cells. These results contribute to a better understanding of the cellular and molecular mechanisms governing human height and can facilitate improved diagnosis and treatment strategies of patients with skeletal growth disorders.

molecular biology↗

bioRxiv2023

Foundation Models Meet Imbalanced Single-Cell Data When Learning Cell Type Annotations

With the emergence of single-cell foundation models, an important question arises: how do these models perform when trained on datasets having an imbalance in cell type distribution due to rare cell types or biased sampling? We benchmark three foundation models, scGPT, scBERT, and Geneformer, using skewed single-cell cell-type distribution for cell-type annotation. While all models had reduced performance when challenged with rare cell types, scGPT and scBERT, performed better than Geneformer. Notably, in contrast to scGPT and scBERT, Geneformer uses ordinal positions of the tokenized genes rather than actual raw gene expression values. To mitigate the effect of a skewed distribution, we find that random oversampling, but not random undersampling, improved the performance for all three foundation models. Finally, scGPT, using FlashAttention, has the fastest computational speed, whereas scBERT is more memory-efficient. We conclude that tokenization and data representation are essential areas of research, and new strategies are needed to mitigate the effects of imbalanced learning in single-cell foundation models. Code and data for reproducibility are available at https://github.com/SabbaghCodes/ImbalancedLearningForSingleCellFoundationModels.

bioinformatics↗

bioRxiv2021

DNA transposon expansion is associated with genome size increase in mudminnows

Genome sizes of eukaryotic organisms vary substantially, with whole genome duplications (WGD) and transposable element expansion acting as main drivers for rapid genome size increase. The two North American mudminnows, Umbra limi and U. pygmaea, feature genomes about twice the size of their sister lineage Esocidae (e.g., pikes and pickerels). However, it is unknown whether all Umbra species share this genome expansion and which causal mechanisms drive this expansion. Using flow cytometry, we find that the genome of the European mudminnow is expanded similarly to both North American species, ranging between 4.5-5.4 pg per diploid nucleus. Observed blocks of interstitially located telomeric repeats in Umbra limi suggest frequent Robertsonian rearrangements in its history. Comparative analyses of transcriptome and genome assemblies show that the genome expansion in Umbra is driven by extensive DNA transposon expansion without WGD. Furthermore, we find a substantial ongoing expansion of repeat sequences in the Alaska blackfish Dallia pectoralis, the closest relative to the family Umbridae, which might mark the beginning of a similar genome expansion. Our study suggests that the genome expansion in mudminnows, driven mainly by transposon expansion, but not WGD, occurred before the separation into the American and European lineage. Significance StatementNorth American mudminnows feature genomes about twice the size of their sister lineage Esocidae (e.g., pikes and pickerels). However, neither the mechanism underlaying this genome expansion, nor whether this feature is shared amongst all mudminnows is currently known. Using cytogenetic analyses, we find that the genome of the European mudminnow also expanded and that extensive chromosome fusion events have occurred in some Umbra species. Furthermore, comparative genomics based on de-novo assembled transcriptomes and genome assemblies, which have recently become available, indicates that DNA transposon activity is responsible for this expansion.

evolutionary biology↗