Biology subjects

Meer, M.

Publications and source records attributed to Meer, M..

7 recordsLinked to original sources

bioRxiv2024

Spns1-dependent endocardial lysosomal function drives valve morphogenesis through Notch1-signaling.

Autophagy-lysosomal degradation is an evolutionarily conserved process key to cellular homeostasis, differentiation, and stress survival, which is particularly important for the cardiovascular system. Furthermore, experimental and clinical observations indicate it affects cardiac morphogenesis, including valve development. However, the cell-specificity and functional role of autophagic processes during heart development remain unclear. Here, we introduce novel zebrafish models to visualize autophagic vesicles in vivo and follow their temporal and cellular localization in the larval heart. We observed a significant accumulation of lysosomal vesicles in the developing atrioventricular and bulboventricular regions and their respective valves. Next, we addressed the role of lysosomal degradation using a Spinster homolog 1 (spns1) mutant. spns1 mutants displayed morphological and functional cardiac defects, including abnormal endocardial organization, impaired valve formation and retrograde blood flow. Single-nuclear transcriptome analysis revealed endocardial-specific differences in the expression of lysosome-related genes and alterations of notch1-signalling in the mutant. Endocardial-specific overexpression of spns1 and notch1 rescued features of valve formation and function. Altogether, our study reveals a cell-autonomous role of lysosomal processing during cardiac valve formation upstream of notch1-signalling.

developmental biology↗

bioRxiv2023

Systems Age: A single blood methylation test to quantify aging heterogeneity across 11 physiological systems

Individuals, organs, tissues, and cells age in diverse ways throughout the lifespan. Epigenetic clocks attempt to quantify differential aging between individuals, but they typically summarize aging as a single measure, ignoring within-person heterogeneity. Our aim was to develop novel systems-based methylation clocks that, when assessed in blood, capture aging in distinct physiological systems. We combined supervised and unsupervised machine learning methods to link DNA methylation, system-specific clinical chemistry and functional measures, and mortality risk. This yielded a panel of 11 system-specific scores- Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone, and Metabolic. Each system score predicted a wide variety of outcomes, aging phenotypes, and conditions specific to the respective system. We also combined the system scores into a composite Systems Age clock that is predictive of aging across physiological systems in an unbiased manner. Finally, we showed that the system scores clustered individuals into unique aging subtypes that had different patterns of age-related disease and decline. Overall, our biological systems based epigenetic framework captures aging in multiple physiological systems using a single blood draw and assay and may inform the development of more personalized clinical approaches for improving age-related quality of life.

systems biology↗

bioRxiv2022

FGF8 induces chemokinesis and regulates condensation of mouse nephron progenitor cells

Kidneys develop via iterative branching of the ureteric epithelial tree and subsequent nephrogenesis at the branch points. Nephrons form in the cap mesenchyme as the metanephric mesenchyme (MM) condenses around the epithelial ureteric buds (UBs). Previous work demonstrated that FGF8 is important for the survival of nephron progenitor cells (NPCs), and early deletion of Fgf8 leads to the cessation of nephron formation, which results in post-natal lethality. We now reveal a novel function of FGF8. By combining transgenic mouse models, quantitative imaging assays, and data-driven computational modelling, we show that FGF8 has a strong chemokinetic effect and that this chemokinetic effect is important for the condensation of NPCs to the UB. The computational model shows that the motility must be lower close to the UB to achieve NPC attachment. We conclude that the FGF8 signalling pathway is crucial for the coordination of NPCs behaviour to the UB. Chemokinetic effects have been described also for other FGFs and may be relevant more generally for the formation of mesenchymal condensations.

developmental biology↗

bioRxiv2021

Aging predisposes B cells to malignancy by activating c-Myc and perturbing the genome and epigenome

While cancer is an age-related disease, many cancer studies utilize younger animal models. Here, we uncover how a cancer, B-cell lymphoma, develops as a consequence of a naturally aged system. We show that this malignancy is associated with increased cell size, splenomegaly, and a newly discovered age-associated clonal B-cell (ACBC) population. Driven by exogenous c-Myc activation, hypermethylated promoters and somatic mutations, ACBC cells clonally expand independent of germinal centers (IgM+) and show increased biological age and hypomethylation in partially methylated domains related to mitotic solo-CpGs. Epigenetic changes in transformed mouse B cells are enriched for changes observed in human B-cell lymphomas. Mechanistically, the data suggest that cancerous ACBC cells originate from age-associated B cells, in part involving CD22 protein signaling fostered by the aging microenvironment. Transplantation assays demonstrate that ACBC evolve to become self-sufficient and support malignancy when transferred into young recipients. Inhibition of mTOR or c-Myc in old mice attenuates premalignant changes in B cells during aging and emerges as a therapeutic strategy to delay the onset of age-related lymphoma. Together, we show how aging contributes to B-cell lymphoma through a previously unrecognized mechanism involving cell-intrinsic changes and the aged microenvironment, characterize a model that captures the origin and progression of spontaneous cancer during aging and identify candidate interventions against age-associated lymphoma.

cancer biology↗

bioRxiv2020

A DNAmRep epigenetic fingerprint for determining cellular replication age

ii.Aging is known to elicit dramatic changes to DNA methylation (DNAm), although the causes and consequences of such alterations are not clear and require further exploration. Our ability to experimentally uncover mechanisms of epigenetic aging will be greatly enhanced by our ability to study and manipulate these changes using in vitro models. However, it remains unclear whether the changes elicited by cells in culture can serve as a model of what is observed in aging tissues in vivo. To test this, we serially passaged mouse embryonic fibroblasts (MEFs) and assessed changes in DNAm at each time-point via RRBS. By developing a measure that tracked cellular aging in vitro, we tested whether it tracked physiological aging in various mouse tissues and whether anti-aging interventions modulate this measure. Our measure, termed DNAmCULTURE, was shown to strongly increase with age when examined in multiple tissues (liver, lung, kidney, blood, and adipose). As a control, we confirmed that the measure was not a marker of cellular senescence, suggesting that it reflects a distinct yet progressive cellular aging phenomena that can be induced in vitro. Furthermore, we demonstrated slower epigenetic aging in animals undergoing caloric restriction and a resetting of our measure in lung and kidney fibroblasts when re-programmed to iPSCs. Enrichment and clustering analysis implicated SUZ12, EED and Polycomb group (PcG) factors as potentially important chromatin regulators in translational culture aging phenotypes. Overall, this study supports the concept that physiologically relevant aging changes can be induced in vitro and moving forward, used to uncover mechanistic insights into epigenetic aging.

pathology↗

bioRxiv2020

A rat epigenetic clock recapitulates phenotypic aging and co-localizes with heterochromatin-associated histone modifications

Aging has been shown to be a strong driver of DNA methylation changes, leading to the development of robust biomarkers in humans and more recently, in mice. This study aimed to generate a novel epigenetic clock in rats--a model with unique physical, physiological, and biochemical advantages for studying mammalian aging. Additionally, we incorporated behavioral data, unsupervised machine learning, and network analysis to identify epigenetic signals that not only track with age, but also relate to phenotypic aging and reflect higher-order molecular aging changes. We used DNAm data from reduced representation bisulfite sequencing (RRBS) to train an epigenetic age (DNAmAge) measure in Fischer 344 CDF (F344) rats. In an independent sample of n=32 F344 rats, we found that this measure correlated with age at (r=0.93), and related to physical functioning (5.9e-3), after adjusting for age and differential cell counts. DNAmAge was also found to correlate with age in C57BL/6 mice (r=0.79), and was decreased in response to caloric restriction (CR), such that the longer the animal was on a CR diet, the greater the decrease in DNAm. We also observed resetting of DNAm when kidney and lung fibroblasts when converted to induced pluripotent stem cells (iPSCs). Using weighted gene correlation network analysis (WGCNA) we identified two modules that appeared to drive our DNAmAge measure. These two modules contained CpGs in intergenic regions that showed substantial overlap with histone marks H3K9me3, H3K27me3, and E2F1 transcriptional factor binding. In moving forward, our ability to unravel the complex signals linking DNA methylation changes to functional aging would require experimental studies in model systems in which longitudinal epigenetic changes can be related to other molecular and physiological hallmarks of aging.

molecular biology↗

bioRxiv2019

Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1-3. Changes to DNA methylation patterns over time form the basis of an ageing clock4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns dont just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

molecular biology↗