Biology subjects

Dror, E.

Publications and source records attributed to Dror, E..

4 recordsLinked to original sources

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↗

bioRxiv2017

The Polycomb-dependent epigenome controls β-cell dysfunction, dedifferentiation and diabetes

Chromatin is the physical template that stabilizes and specifies transcriptional programs. To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combined deep epigenome mapping with single cell transcriptomics to mine for evidence of chromatin dysregulation in type-2 diabetes. We identify two chromatin-state signatures that track the trajectory of {beta}-cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-domains and a loss of expression at a subclass of highly active domains containing key lineage-defining genes. {beta}-cell specific deletion of Polycomb (Eed/PRC2) triggers parallel transcriptional signatures. Intriguingly, these {beta}-cell Eed-knockouts also exhibit highly penetrant hyperglycemia-independent dedifferentiation indicating that Polycomb dysregulation sensitizes the {beta}-cell for dedifferentiation. These findings provide novel resources for exploring transcriptional and epigenetic control of {beta}-cell (dys)function. They identify PRC2 as necessary for long-term maintenance of {beta}-cell identity. The data suggest a two-hit model for loss of {beta}-cell identity in diabetes and highlight epigenetic therapeutic potential to block dedifferentiation.

genomics↗