Biology subjects

Jorgensen, K.

Publications and source records attributed to Jorgensen, K..

9 recordsLinked to original sources

bioRxiv2026

SQSTM1/p62 accumulation is a hallmark of FLCN loss in Birt-Hogg-Dube syndrome-associated kidney cancer

Birt-Hogg-Dube syndrome (BHD) is an autosomal, dominant condition caused by Folliculin (FLCN) mutation and characterized by enhanced risk for kidney tumors. Previous studies have shown constitutive nuclear localization of the transcription factor TFEB and simultaneous hyperactivation of canonical MTORC1 signaling in the absence of FLCN. Here we assess the impact on autophagy under this situation of combined anabolic and catabolic activation. Using an established BHD patient-derived kidney cancer cell line, we confirmed that TFEB was permanently localized in the nucleus combined with an increase in canonical MTORC1 signaling, whereas bulk autophagy flux and LC3 lipidation was unaffected by FLCN status. However, we found that the autophagy receptor SQSTM1/p62 accumulated in enlarged puncta in the absence of FLCN. Finally, we recapitulate these findings in a Norwegian cohort of BHD kidney tumor samples. Our results demonstrate SQSTM1/p62 accumulation as a hallmark of FLCN loss, although SQSTM1/p62 appeared dispensable for anchorage-independent growth.

cancer biology↗

bioRxiv2025

Maternal CENP-C restores centromere symmetry in mammalian zygotes to ensure proper chromosome segregation

Across metazoan species, the centromere-specific histone variant CENP-A is essential for accurate chromosome segregation, yet its regulation at the parental-to-zygote transition in mammals is poorly understood. To address this, we developed a CENP-A-mScarlet knock-in mouse model, which revealed sex-specific dynamics: mature sperm retains 10% of the CENP-A levels present in MII-oocytes. However, in zygotes prior to the first mitosis, this difference is resolved, using maternally inherited cytoplasmic-CENP-A. Notably, the increase in CENP-A at paternal centromeres is independent of sensing CENP-A asymmetry or the presence of maternal chromosomes. Instead, CENP-A equalization relies on asymmetric recruitment of maternal CENP-C to paternal centromeres. Depletion of maternal CENP-A decreases total CENP-A in pronuclei without disrupting equalization. In contrast, reducing maternal CENP-C or disruption of its dimerization domains impairs CENP-A equalization and chromosome segregation. Therefore, maternal CENP-C acts a key epigenetic regulator that resets centromeric symmetry at fertilization to preserve genome integrity. Highlights[bullet] CENP-A asymmetry between sperm and oocyte centromeres is a conserved feature from flies to mammals including mice and humans. [bullet]CENP-A asymmetry between parental centromeres is resolved prior to the first zygotic division via maternally inherited, cytoplasmic CENP-A. [bullet]Zygotic CENP-A levels in zygotes are regulated in a pronucleus-autonomous manner. [bullet]CENP-A equalization relies on asymmetric CENP-C recruitment to the paternal pronucleus and requires CENP-C dimerization. Key TermsCentromere; CENP-A; CENP-C; sperm; oocyte; zygote; intergenerational; epigenetics; mouse

genetics↗

bioRxiv2025

Opposing responses of hippocampal theta oscillations to running and a forelimb-dominated sensorimotor behavior

Hippocampal theta oscillations regulate the timing of neurons to support navigation, memory formation, and sensorimotor integration. Theta is modulated by running speed, breathing, whisking, and jumping and increases in tasks involving memory encoding or retrieval. The positive relationship between theta frequency and running speed is believed stabilize hippocampal representations of space amid movement variability. Here, we incorporated a novel string-pulling task to determine if established relationships between movement and theta hold when progress to a reward is determined by the length of string pulled. This task eliminates many speed-associated inputs, such vestibular, visual, and hindlimb information, and allows an unprecedented level of precision in the analysis of individual paw movements. Given that animals move the string a fixed length to acquire a reward, we predicted that the positive relationship between theta frequency and speed would hold. ApproachFive Sprague Dawley rats (4 mo.) were trained to continuously pull a string a fixed distance of 208 cm using an automated string-pulling system and run on a track for food reward. Local-field data was acquired from electrodes in dorsal CA1. ResultsRelationships between theta and movement speed were distinct during string pulling and running. While theta was robust in both conditions, frequency was significantly reduced during string-pulling and showed no speed-frequency coupling, unlike running. This difference could result from the conflict between hindlimb and forelimb signals, with only forelimb movement signaling advancement. Fine-grained analysis of paw movements during string-pulling (lift, advance, grasp, pull, push) revealed that theta power and frequency peaked during the contralateral paws downward push despite paw speed being low during this action. This suggests that theta frequency and power could respond to effort rather than purely kinematic information. Notably, running-associated theta may similarly reflect both speed and effort as most locomotor tasks conflate these variables. Finally, theta phase aligned from one reach-pull cycle to the next during the downward pull motion - the first action that directly advances the string forward. Since phase-locking has been associated with sensorimotor gating, synchrony at this point could reflect the gating of inputs that are the most causally relevant for reaching the reward, potentially facilitating integration of action-outcome signals for memory encoding and navigation. Taken together, these data support a dual-scale view of hippocampal processing and theta-band activity where macroscale theta activity requires suprathreshold sensory, vestibular, and proprioceptive drive and microscale theta remains sensitive to subsecond limb movements.

neuroscience↗

bioRxiv2025

Thalamic Nuclei Volumes Across Psychiatric and Neurological Disorders: A Multi-Site Magnetic Resonance Imaging Study

The human thalamus is an integrative hub for multiple cortical and subcortical circuits involved in sensory processing and higher cognitive functions. Thalamic volume differences have been reported across multiple psychiatric and neurological disorders, but previous studies have typically relied on small samples, focused on one or a limited number of disorders, or investigated the thalamus as a whole without considering its functional subdivisions. In this multi-site study, we compared thalamic nuclei volumes across mild cognitive impairment (MCI), dementia (DEM), major depressive disorder, schizophrenia spectrum disorder (SCZ), clinical high risk for schizophrenia, bipolar spectrum disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder, Parkinsons disease, multiple sclerosis (MS), and healthy controls (N > 8 000). Using structural MRI, we segmented 25 bilateral thalamic nuclei, corresponding to six anatomical groups. Linear models revealed that anterior, medial and lateral regions of the thalamus were significantly smaller in several conditions, with largest effects observed for MCI, DEM, SCZ and MS. In contrast, the ventral and intralaminar groups were relatively normal. This pattern of effects largely corresponds to the canonical functional subdivision of the thalamus into higher-order and sensory regions. At the level of individual nuclei, the clinical conditions were associated with distinct patterns of alterations, while left and right lateral geniculate nuclei were implicated in six of the disorders, suggesting a possible relation with circadian and sleep disturbances. Together, the results highlight a role for the higher-order thalamus in common brain disorders and a differential involvement at the nuclei level, refining our understanding of thalamic pathology across common brain disorders.

neuroscience↗

bioRxiv2025

Adaptive Increase of Amylase Gene Copy Number in Peruvians Driven by Potato-rich Diets

Summary/AbstractThe salivary amylase gene (AMY1) exhibits remarkable copy number variation linked to dietary shifts in human evolution. While global studies highlight its structural complexity and association with starch-rich diets, localized selection patterns remain under explored. Here, we analyzed AMY1 copy number in 3,723 individuals from 85 populations, revealing that Indigenous Peruvian Andean populations possess the highest AMY1 copy number globally. A genome-wide analysis showed significantly higher amylase copy numbers in Peruvian Andean genomes compared to closely related populations. Further, we identified positive selection (selection coefficient of 0.0124, log likelihood ratio of 11.1543) at the nucleotide level on a haplotype harboring at least five haploid AMY1 copies, with a Peruvian Andean-specific expansion coinciding with potato domestication ([~]6-10 kya). Using ultra-long-read sequencing, we demonstrated that previously described recombination-based mutational mechanisms drive the formation of high-copy AMY1 haplotypes observed in Andean population. Our study provides a framework for investigating structurally complex loci and their role in human dietary adaptation.

genetics↗

bioRxiv2024

Stepwise neofunctionalization of the NF-κB family member c-Rel during vertebrate evolution

Adaptive immunity and the five vertebrate NF-{kappa}B/Rel family members first appeared in cartilaginous fish, suggesting that divergence and specialization within the NF-{kappa}B family helped facilitate the evolution of adaptive immunity. One specialized function of the NF-{kappa}B c-Rel protein in macrophages is the activation of Il12b, which encodes a key regulator of T-cell development. We found that c-Rel is a far more potent regulator of Il12b than of any other inducible genes in macrophages, with c-Rel regulation of Il12b dependent on its heightened intrinsic DNA-binding affinity. c-Rel homodimers regulate Il12b transcription in part via motifs with little resemblance to canonical NF-{kappa}B motifs. ChIP-seq experiments further defined distinct c-Rel DNA-binding preferences genome-wide, and X-ray crystallography of a c-Rel/RelA chimeric protein identified key amino acid changes that support the unique c-Rel properties. Unexpectedly, these changes, along with the c-Rel/RelA binding affinity differences, were largely restricted to mammalian species. Together, our findings reveal how a transcription factor family member can undergo a structural transition at a late stage of vertebrate evolution, resulting in an increased intrinsic DNA binding affinity and with clear functional consequences, presumably to support the increasing complexity of immune regulation.

immunology↗

bioRxiv2023

De novo genome assembly of four Andean potato weevil species (Premnotrypes,Rhigopsidius), the primary agricultural pest of the potato in South America

The Andean potato weevil complex are the most widespread and serious insect pests to potato crops in the Andes. More broadly, genomic assemblies of insect pests are currently lacking in agricultural research, especially those from the order Coleoptera. These genome data are essential for identifying potential underlying mechanisms important to biological control strategies and food security in the highlands. Here, we present the de novo genome assemblies for four species of the Andean potato weevil complex: Premnotrypes vorax, P. suturicallus, P. latithorax, and Rhigopsidius piercei. Genome assemblies exceeded the average size of those from the order Coleoptera and were highly repetitive: for P. vorax (1.33 Gb, 71.51% repetitive), P. latithorax (623 Mb, 59.03% repetitive), P. suturicallus (1.23 Gb, 70.19% repetitive), and R. piercei (1.55 Gb, 71.91% repetitive). We examined genomic regions related to metabolic potato plant detoxification and insecticide resistance using the available Colorado potato beetle (Leptinotarsa decemlineata) genome annotations as a guide. Our analysis of these weevil genomes identified chemosensory receptors and odorant binding proteins that could be related to detecting their hosts, the potato plant (Solanum tuberosum), as well as many genomic regions involved in subverting pesticide resistance. We have generated the first whole-genome assemblies of the Andean potato weevil complex that will be foundational for future agricultural pest management and entomological research in South America. Author SummaryWithin the South American Andean mountains the Andean potato weevil insects are the most widespread and serious pests to potatoes, destroying around 89% of potato harvests a year when insecticides are not used. Here, we collected and performed whole-genome sequencing for the first time for four Andean potato weevil species: Premnotrypes vorax, P. suturicallus, P. latithorax, and Rhigopsidius piercei. After analysis of these genome assemblies, we found that they were large and highly repetitive compared to other published beetle genome data in the order Coleoptera. After further examination of these genome assemblies, we found regions related to metabolic potato plant detoxification, insecticide resistance, and chemosensory and odorant binding protein receptors that could be related to detecting potato plants. These genomic identifications provide novel molecular insight into regions associated with insecticide resistance, metabolic abilities, and environmental receptors, and can serve as a future valuable resource in classifying phylogenetic relationships as well as identifying regions of interest for improved pest management for potato farmers.

genomics↗

bioRxiv2022

Equalizing epigenetically imprinted centromeres in early mammalian embryos

The CENP-A histone variant epigenetically defines centromeres, where its levels and locations are precisely maintained through mitotic cell divisions. However, differences in centromere CENP-A propagation in soma versus female/male germline remains poorly understood. Here, we generated CenpamScarlet mice and followed CENP-A dynamics in gametes, zygotes, and embryos. We found that, unlike somatic cells, progenitor female and male germ cells carry high centromeric CENP-A levels that decrease upon terminal differentiation. The reduction in CENP-A is differentially regulated between sexes, resulting in a ten-fold higher level in oocytes compared to sperm. In the zygote, the parent-of-origin CENP-A asymmetry is equalized prior to initial S-phase by redistribution of nuclear CENP-A from maternal to paternal chromosomes. Redistribution of CENP-A requires both CDK1/2 and PLK1 centromeric machinery. These experiments provide direct evidence for resetting of epigenetically imprinted centromeres in early pronuclear stage embryos and imply a mechanism to sense the non-equivalency of parental chromosomes. HighlightsO_LIIncreased CENP-A density at centromeres is a conserved property of germline stem cells while CENP-A reduction is coincident with germ cell differentiation C_LIO_LIPaternal and maternal CENP-A containing nucleosomes are intergenerationally inherited C_LIO_LICENP-A density at centromeres differs between male and female mature gametes C_LIO_LIUpon fertilization, maternal nuclear CENP-A is redistributed to equalize with parental CENP-A C_LIO_LICENP-C and MIS18BP1 are asymmetrically enriched in the parental pronuclei in accordance with CENP-A asymmetry. C_LIO_LILicensing for centromere equalization begins before zygotic DNA replication C_LI

developmental biology↗

bioRxiv2021

Single residue substitution in protamine 1 disrupts sperm genome packaging and embryonic development in mice

Conventional dogma presumes that protamine-mediated DNA compaction in sperm is achieved by passive electrostatics between DNA and the arginine-rich core of protamines. However, phylogenetic analysis reveals several non-arginine residues that are conserved within, but not across, species. The functional significance of these residues or post-translational modifications are poorly understood. Here, we investigated the functional role of K49, a rodent-specific lysine residue in mouse protamine 1 (P1) that is acetylated early in spermiogenesis and retained in sperm. In vivo, an alanine substitution (P1 K49A) results in ectopic histone retention, decreased sperm motility, decreased male fertility, and in zygotes, premature P1 removal from paternal chromatin. In vitro, the P1 K49A substitution decreases protamine-DNA binding and alters DNA compaction/decompaction kinetics. Hence, a single amino acid substitution outside the P1 arginine core is sufficient to profoundly alter protein function and developmental outcomes, suggesting that protamine non-arginine residues are essential to ensure reproductive fitness.

biochemistry↗