Biology subjects

Petri, A.

Publications and source records attributed to Petri, A..

8 recordsLinked to original sources

bioRxiv2026

A positively selected microRNA controls a reversible aging program in striated muscle

Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies.

molecular biology↗

bioRxiv2024

circPCMTD1: A protein-coding circular RNA that regulates DNA damage response in BCR/ABL-positive leukemias

Circular RNAs are a novel class of RNA transcripts, which regulate important cellular functions in health and disease. Herein, we report on the functional relevance of the circPCMTD1 transcript in acute leukemias. In screening experiments, we found that circPCMTD1 depletion strongly inhibited the proliferative capacity of leukemic cells with BCR-ABL translocations. Mass cytometry experiments identified the aberrant activation of the DNA damage response as an early downstream event of circPCMTD1 depletion. In in vivo experiments, circPCMTD1 targeting prolonged the survival of mice engrafted with leukemic blasts harboring the Philadelphia chromosome. Mechanistically, we found that circPCMTD1 was enriched in the cytoplasm and associated with the ribosomes of the leukemic cells. We detected a cryptic open reading frame within the circPCMTD1 sequence and found that circPCMTD1 could generate a peptide product. The circPCMTD1-derived peptide interacted with proteins of the BTR complex and enhanced BTR complex formation, thereby increasing tolerance to genotoxic stress.

cancer biology↗

bioRxiv2023

Ecological genomics in the Northern krill uncovers loci for local adaptation across ocean basins

Krill is a vital food source for many marine animals but also strongly impacted by climate change. Genetic adaptation could support populations, but remains uncharacterized. We assembled the 19 Gb Northern krill genome and compared genome-scale variation among 74 specimens from the colder Atlantic Ocean and warmer Mediterranean Sea. The genome is dominated by methylated transposable elements and contains many duplicated genes implied in molting and vision. Analysis of 760 million SNPs indicates extensive homogenizing gene-flow among populations. Nevertheless, we detect extreme divergence across hundreds of genes, governing ecophysiological functions like photoreception, circadian regulation, reproduction and thermal tolerance. Such standing variation may be essential for resilience in zooplankton, necessitating insight into adaptive variation to forecast their roles in future marine ecosystems and support ocean conservation. One-Sentence SummaryGenome-scans of Northern krill link genes for photoreception, reproduction and thermal tolerance to ecological adaptation.

evolutionary biology↗

bioRxiv2021

Inversions maintain differences between migratory phenotypes of a songbird

Long-distance migration requires adaptations in a suite of behavioral, physiological and morphological traits. However, almost nothing is known about the genetic basis of these adaptations. The willow warbler Phylloscopus trochilus occurs in Europe with a northern and southern subspecies that show drastically different migration routes and wintering areas. Previous studies have demonstrated that the subspecies are genetically extremely similar except for three divergent chromosome regions, of which two are associated with the differences in migratory phenotypes and one is associated with an environmental gradient. Here we use a combination of long-read sequencing, linked-read sequencing and optical mapping to construct more complete and contiguous assemblies for both of the subspecies. We find evidence for inversions in each of the three divergent regions, which range from 0.4 to 13 Mb in size, and that breakpoints are associated with tandem repeat arrays or segmental duplications. The divergence times between inverted and non-inverted haplotypes are similar across the regions ([~]1.2 Myrs), which is compatible with a scenario where the inversions arose in either of two allopatric populations that subsequently hybridized. The improved genome assemblies and annotation also allowed us to detect additional functional differences in the divergent regions that provide candidate genes for migration and local adaptations to environmental gradients.

evolutionary biology↗

bioRxiv2020

Hematopoietic stem cells fail to regenerate following inflammatory challenge.

Hematopoietic stem cells (HSCs) are canonically defined by their capacity to maintain the HSC pool via self-renewal divisions. However, accumulating evidence suggests that HSC function is instead preserved by sustaining long-term quiescence. Here, we study the kinetics of HSC recovery in mice, following an inflammatory challenge that induces HSCs to exit dormancy. Repeated inflammatory challenge resulted in a progressive depletion of functional HSCs, with no sign of later recovery. Underlying this observation, label retention experiments demonstrated that self-renewal divisions were absent or extremely rare during challenge, as well as during any subsequent recovery period. While depletion of functional HSCs held no immediate consequences, young mice exposed to inflammatory challenge developed blood and bone marrow hypocellularity in old age, similar to elderly humans. The progressive, irreversible attrition of HSC function demonstrates that discreet instances of inflammatory stress can have an irreversible and therefore cumulative impact on HSC function, even when separated by several months. These findings have important implications for our understanding of the role of inflammation as a mediator of dysfunctional tissue maintenance and regeneration during ageing.

cell biology↗

bioRxiv2020

PTENP1-AS contributes to BRAF inhibitor resistance and is associated with adverse clinical outcome in stage III melanoma

Approximately 50% of human cutaneous melanomas carry activating mutations in the serine/threonine protein kinase BRAF. BRAF inhibitors (BRAFi) selectively target the oncogenic BRAFV600E/K and are effective in approximately 80% of patients carrying the mutation. However, resistance to BRAFi is common and emerges within a median time of 6-7 months of treatment and is prolonged to 11 months when combined with MEK inhibitors. Better characterization of the underlying molecular processes is therefore needed to further improve treatments. Inactivation of the tumor suppressor gene PTEN has been suggested to occur during melanomagenesis and drug resistance development. We recently demonstrated that transcription of PTEN is negatively regulated by an antisense RNA from the PTEN pseudogene (PTENP1-AS) and here set out to investigate the impact of this molecular pathway on the resistance to BRAFi and clinical outcome. We used a panel of BRAFi resistant A375 sublines, and observed increased levels of PTENP1-AS associated with reduced expression of PTEN. Furthermore, this loss of PTEN expression was correlated to increased recruitment of Enhancer of zeste homolog 2 (EZH2) and formation of the transcriptional repression mark H3K27me3 at the PTEN promoter in the resistant cells. We demonstrated that targeting of PTENP1-AS was able to re-activate the expression of PTEN and sensitize resistant melanoma cells to BRAFi. Finally, we showed that PTENP1-AS is a promising prognostic marker for clinical outcome in melanoma patients as high expression of PTENP1-AS in regional lymph node metastases from stage III melanoma patients correlated with poor survival.

cancer biology↗

bioRxiv2019

Functional Annotation of Human Long Non-Coding RNAs via Molecular Phenotyping

Long non-coding RNAs (lncRNAs) constitute the majority of transcripts in the mammalian genomes and yet, their functions remain largely unknown. We systematically knockdown 285 lncRNAs expression in human dermal fibroblasts and quantified cellular growth, morphological changes, and transcriptomic responses using Capped Analysis of Gene Expression (CAGE). Antisense oligonucleotides targeting the same lncRNA exhibited global concordance, and the molecular phenotype, measured by CAGE, recapitulated the observed cellular phenotypes while providing additional insights on the affected genes and pathways. Here, we disseminate the largest to-date lncRNA knockdown dataset with molecular phenotyping (over 1,000 CAGE deep-sequencing libraries) for further exploration and highlight functional roles for ZNF213-AS1 and lnc-KHDC3L-2.

genomics↗

bioRxiv2018

De novo transcriptome assembly, annotation, and identification of low-copy number genes in the flowering plant genus Silene (Caryophyllaceae)

Phylogenetic methods that rely on information from multiple, unlinked genes have recently been developed for resolving complex situations where evolutionary relationships do not conform to bifurcated trees and are more adequately depicted by networks. Such situations arise when successive interspecific hybridizations in combination with genome duplications have shaped species phylogenies. Several processes such as homoeolog loss and deep coalescence can potentially hamper our ability to recover the historical signal correctly. Consequently the prospect of reconstructing accurate phylogenies lies in the combination of several low-copy nuclear markers that when, used in concert, can provide homoeologs for all the ancestral genomes and help to disentangle gene tree incongruence due to deep coalescence events. Expressed sequence tag (EST) databases represent valuable resource for the identification of genes in organisms with uncharacterized genomes and for development of molecular markers. The genus Silene L. is a prime example of a plant group whose evolutionary history involves numerous events of hybridization and polyploidization. As for many groups there is currently a shortage of low-copy nuclear markers, for which phylogenetic usefulness has been demonstrated. Here, we present two EST libraries for two species of Silene that belong to large phylogenetic groups not previously investigated with next generation technologies. The assembled and annotated transcriptomes are used for identifying low copy nuclear regions, suitable for sequencing.

bioinformatics↗