Biology subjects

Jankowski, A.

Publications and source records attributed to Jankowski, A..

4 recordsLinked to original sources

bioRxiv2025

ER stress and cell fate: FKBP2 regulates proinsulin folding and α- vs. β-cell differentiation via NFAT and HDAC9

The continuous demand for insulin production places a burden on the endoplasmic reticulum (ER) of pancreatic {beta} cells, making them highly susceptible to protein misfolding and ER stress. While general ER chaperones are known to be essential for {beta} cell homeostasis, the specific mechanisms by which individual chaperones facilitate proinsulin folding and influence cell fate remain unclear. This study identifies FK506-binding protein 2 (FKBP2), an ER-localized cis-trans prolyl isomerase, as a critical regulator of human {beta} cell differentiation and proinsulin processing. Using loss- and gain-of-function FKBP2 models in human pluripotent stem cells (hPSCs), we demonstrate that its deficiency impairs insulin processing, leading to abnormal insulin granule morphology and reduced insulin secretion. Unexpectedly, our findings reveal a crucial and unreported role for FKBP2 in cell fate determination. Single-cell RNA sequencing reveals that FKBP2 loss disrupts the proper endocrine lineage allocation, causing a shift towards the cell formation at the expense of {beta} cells. In KO endocrine cells, we observed sustained ER stress and elevated intracellular calcium levels, along with activation of the NFAT2-HDAC9 axis. Pharmacological inhibition of HDAC class IIa activity partially rescued {beta} cell differentiation, supporting a causal role for this pathway. Collectively, our results provide new mechanistic insights into how ER chaperones can control pancreatic development and contribute to the pathogenesis of diabetes.

cell biology↗

bioRxiv2025

Trans-homologous interactions identified in Hi-C data are associated with embryonic development

Interactions between chromosomes forming homologous pairs are known to be widespread in the fruit fly Drosophila melanogaster and present in other organisms. While these trans-homologous interactions affect regulation of gene expression, many details regarding their location, function and mechanisms of action are still unknown. The increased availability of phased Hi-C datasets made it possible to reliably infer such trans-homologous interactions. We have developed a tool called TransContactHiC to detect trans-homologous chromatin interactions in phased Hi-C data and we used it to re-analyze published in situ Hi-C data for heterozygotic Drosophila melanogaster cells: embryos and a fully differentiated cell line. We further assessed the frequency of cis- and trans-homologous interactions for equally sized genomic bins, and detected triads of genomic elements which exhibit significantly different frequency of trans-homologous interactions compared to the cis-homologous counterpart. We show that triads of genomic elements exhibiting significantly higher frequency of trans homologous interactions are characterized by their clustering within broader regulatory regions, proximity to DNase-seq peaks and presence of disrupted transcription factor motifs at the affected locus. We also show examples of annotated active cis-regulatory modules which might be affected by these differential trans-homologous interactions. Overall, our results show the functional relevance of the detected triads.

genomics↗

bioRxiv2024

Tracking changes in functionality and morphology of repopulated microglia in young and old mice

Microglia (MG) are myeloid cells of the central nervous system supporting its homeostasis and instigating neuroinflammation in pathologies. Single-cell RNA sequencing (scRNA-seq) revealed the functional heterogeneity of MG in mice brains. Inhibition of colony-stimulating factor 1 receptor (CSF1R) signaling with inhibitors deplete microglia which rapidly repopulate. Functionalities of repopulated microglia are poorly known. We combined scRNA-seq, bulk RNA-seq, immunofluorescence and confocal imaging to study functionalities and morphology of repopulated microglia. CSRF1R inhibitor (BLZ-945) depleted MG in 21 days and their numbers were restored 7 days later as evidenced by TMEM119 staining and flow cytometry. ScRNA-seq and computational analyses demonstrate that repopulated MG originate from preexisting MG progenitors and reconstitute functional clusters but upregulate inflammatory genes. Percentages of proliferating, immature MG displaying inflammatory gene expression increase in aging mice. Morphometric analysis of MG cell body and branching shows distinct morphology of repopulated MG, particularly in old mouse brains. We demonstrate that with aging some repopulated MG fail to reach the homeostatic phenotype. These differences microglia may contribute to the deterioration of microglia protective functions with age.

neuroscience↗

bioRxiv2022

New enhancer-promoter interactions are gained during tissue differentiation and reflect changes in E/P activity

To regulate gene expression, enhancers must come into proximity with their target gene. At some loci the timing of enhancer-promoter proximity is uncoupled from gene activation, while at others it is tightly linked. Here, we assessed this more globally for 600 characterized enhancers or promoters (E/P) with tissue-specific activity in Drosophila embryos, by performing Capture-C and insulator ChIP in FACS-purified myogenic or neurogenic cells at different stages of embryogenesis. This high-resolution view enabled direct comparison between E/P interactions and activity across 5 developmental conditions. This revealed largely invariant E/P contacts between the blastoderm and cell fate specification stages, despite changes in activity. However, E/P interactions diverge during terminal tissue differentiation when many tissue-specific interactions are gained on top of a pre-existing topology. Changes in E/P proximity reflect changes in enhancer activity and gene activation, and are generally not accompanied by changes in insulator binding. Using transgenes and deletions, we show that many tissue-specific interactions represent functional E-P pairs. Our results reveal a shift in E-P landscapes as embryogenesis proceeds, from largely pre-formed topologies at early stages to more distal tissue-specific loops during differentiation, when E/P proximity appears coupled to activation.

developmental biology↗