Biology subjects

Panzeri, I.

Publications and source records attributed to Panzeri, I..

6 recordsLinked to original sources

bioRxiv2024

Chronic obesity does not alter cancer survival in Tp53R270H/+ mice

Obesity is a complex chronic disease characterized by excessive adiposity and associations with numerous co-morbidities, including cancer. Despite extensive research, we have limited understanding of the mechanisms coupling obesity to cancer risk, and separately, of the contexts where obesity does or does not exacerbate disease. Here, we show that chronic high-fat diet induced obesity has no significant effect on the Trp53R270H/+ mouse, a model of human Li-Fraumeni multi-cancer syndrome. Surprisingly, despite inducing rapid and highly penetrant obesity and long-term differences in adiposity, greater than one year of HFD had no significant effect on survival or tumor burden. These findings were replicated in two separate cohorts totaling 359 mice and thus provide important negative data for the field. Given strong publication bias against negative data in the literature, this large murine cohort study represents a clear case where chronic diet-induced obesity does not accelerate or aggravate cancer outcomes. The data thus carry high impact for researchers, funders, and policymakers alike.

cancer biology↗

bioRxiv2023

Developmental priming of cancer susceptibility

DNA mutations are necessary drivers of cancer, yet only a small subset of mutated cells go on to cause the disease. To date, the mechanisms that determine which rare subset of cells transform and initiate tumorigenesis remain unclear. Here, we take advantage of a unique model of intrinsic developmental heterogeneity (Trim28+/D9) and demonstrate that stochastic early life epigenetic variation can trigger distinct cancer-susceptibility states in adulthood. We show that these developmentally primed states are characterized by differential methylation patterns at typically silenced heterochromatin, and that these epigenetic signatures are detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential. These same genes are frequently mutated in human cancers, and their dysregulation correlates with poor prognosis. These results provide proof-of-concept that intrinsic developmental heterogeneity can prime individual, life-long cancer risk.

cancer biology↗

bioRxiv2023

A rapid microglial metabolic response controls metabolism and improves memory

Chronic high-fat feeding triggers chronic metabolic dysfunction including obesity, insulin resistance, and diabetes. How high-fat intake first triggers these pathophysiological states remains unknown. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on metabolism and spatial / learning memory. High-fat intake rapidly increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation and fission as well as metabolic skewing towards aerobic glycolysis. These effects are detectable throughout the brain and can be detected within as little as 12 hours of HFD exposure. In vivo, microglial ablation and conditional DRP1 deletion show that the microglial metabolic response is necessary for the acute effects of HFD. 13C-tracing experiments reveal that in addition to processing via {beta}-oxidation, microglia shunt a substantial fraction of palmitate towards anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuro-protective metabolite itaconate. Together, these data identify microglia as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and releasing the same carbons as alternate bioenergetic and protective substrates for surrounding cells. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/535373v2_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@1b9699corg.highwire.dtl.DTLVardef@1c48efcorg.highwire.dtl.DTLVardef@18757d0org.highwire.dtl.DTLVardef@962cf6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

Identification of two β-cell subtypes by 7 independent criteria

Despite the recent explosion in surveys of cell-type heterogeneity, the mechanisms that specify and stabilize highly related cell subtypes remain poorly understood. Here, focusing initially on exploring quantitative histone mark heterogeneity, we identify two major sub-types of pancreatic {beta}-cells ({beta}HI and {beta}LO). {beta}HI and {beta}LO cells differ in their size, morphology, cytosolic and nuclear ultrastructure, transcriptional output, epigenomes, cell surface marker, and function. Importantly, {beta}HI and {beta}LO cells can be FACS separated live into CD24+ ({beta}HI) and CD24- ({beta}LO) fractions. From an epigenetic viewpoint, {beta}HI-cells exhibit [~]4-fold higher levels of H3K27me3, more compacted chromatin, and distinct chromatin organization that associates with a specific pattern of transcriptional output. Functionally, {beta}HI cells have increased mitochondrial mass, activity, and insulin secretion both in vivo and ex vivo. Critically, Eed and Jmjd3 loss-of-function studies demonstrate that H3K27me3 dosage is a significant regulator of {beta}HI / {beta}LO cell ratio in vivo, yielding some of the first-ever specific models of {beta}-cell sub-type distortion. {beta}HI and {beta}LO sub-types are conserved in humans with {beta}HI-cells enriched in human Type-2 diabetes. These data identify two novel and fundamentally distinct {beta}-cell subtypes and identify epigenetic dosage as a novel regulator of {beta}-cell subtype specification and heterogeneity. HighlightsO_LIQuantitative H3K27me3 heterogeneity reveals 2 common {beta}-cell subtypes C_LIO_LI{beta}HI and {beta}LO cells are stably distinct by 7 independent sets of parameters C_LIO_LIH3K27me3 dosage controls {beta}HI / {beta}LO ratio in vivo C_LIO_LI{beta}HI and {beta}LO cells are conserved in humans and enriched in Type-2 diabetes C_LI

cell biology↗

bioRxiv2022

Genetic polymorphisms lead to major, locus-specific, variation in piRNA production in mouse.

PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that silence transposons in the animal germline. PiRNAs are produced from long single-stranded non-coding transcripts, from protein-coding transcripts, as well as from transposons. While some sites that produce piRNAs are in deeply conserved syntenic regions, in general, piRNAs and piRNA-producing loci turnover faster than other functional parts of the genome. To learn about the sequence changes that contribute to the fast evolution of piRNAs, we set out to analyse piRNA expression between genetically different mice. Here we report the sequencing and analysis of small RNAs from the mouse male germline of four classical inbred strains, one inbred wild-derived strain and one outbred strain. We find that genetic differences between individuals underlie variation in piRNA expression. We report significant differences in piRNA production at loci with endogenous retrovirus insertions. Strain-specific piRNA-producing loci include protein-coding genes. Our findings provide evidence that transposable elements contribute to inter-individual differences in expression, and potentially to the fast evolution of piRNA-producing loci in mammals.

genomics↗

bioRxiv2018

Ultra-parallel ChIP-seq by barcoding of intact nuclei

Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) is an invaluable tool for mapping chromatin-associated proteins. However, sample preparation is still a largely individual and labor-intensive process that hinders assay throughput and comparability. Here, we present a novel method for ultra-parallelized high-throughput ChIP-seq that addresses the aforementioned problems. The method, called RELACS (Restriction Enzyme-based Labeling of Chromatin in Situ), employs barcoding of chromatin within intact nuclei extracted from different sources (e.g. tissues, treatments, time points). Barcoded nuclei are pooled and processed within the same ChIP, for maximal comparability and significant workload reduction. The choice of user-friendly, straightforward, enzymatic steps for chromatin fragmentation and barcoding makes RELACS particularly suitable for implementation large-scale clinical studies and scarce samples. RELACS can generate ChIP-seq libraries from hundreds of samples within three days and with less than 1000 cells per sample.

genomics↗