Biology subjects

Cannon, G. H.

Publications and source records attributed to Cannon, G. H..

5 recordsLinked to original sources

bioRxiv2025

Liver single-nucleus multiome profiling reveals cell-type mechanisms for cardiometabolic traits

The liver is a central regulator of cardiometabolic physiology, coordinating processes such as lipid and glucose metabolism, protein synthesis, and detoxification. Genome-wide association studies (GWAS) have identified hundreds of genetic variants associated with cardiometabolic traits, yet their molecular mechanisms in liver cell types remain unclear. Using multiome single-nucleus RNA and ATAC sequencing on liver samples from 39 individuals, we profiled gene expression and chromatin accessibility in 68,398 nuclei across six primary liver cell types. We identified 306,706 accessible chromatin regions, including 70,884 regions undetected in bulk tissue analyses and that predominantly represent less abundant cell types. To identify genetic effects on gene regulation in liver cell types, we mapped quantitative trait loci (QTLs) and detected 1,885 chromatin accessibility QTLs (caQTLs) and 67 expression QTLs (eQTLs). We integrated cell-type QTLs with GWAS signals and revealed cell types, genes, and chromatin regulatory elements involved in cardiometabolic traits, such as liver enzyme and cholesterol levels. Non-hepatocyte cell-type QTL analyses exposed previously obscured mechanisms, such as an eQTL for ADAMTS12 in liver sinusoidal endothelial cells potentially involved in liver fibrosis, demonstrating that single-nucleus approaches can capture regulatory events missed in bulk analyses. Furthermore, we predicted cell type of action for bulk liver caQTLs colocalized with GWAS signals, enhancing mechanistic insights for complex trait associations. Our findings provide a high-resolution map of the hepatic regulatory landscape and advance the understanding of cellular contexts and molecular mechanisms underlying cardiometabolic traits.

genomics↗

bioRxiv2021

Ret loss-of-function decreases enteric neural crest progenitor proliferation and restricts developmental fate potential during enteric nervous system development

The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest-derived cells (ENCDCs) during enteric nervous system (ENS) development. Pathogenic RET loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCDCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single- cell RNA sequencing (scRNA-seq) on an enriched population of ENCDCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCDCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCDC with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes associated with the proper development of the ENS, including the specification of inhibitory neuron subtypes, cell cycle dynamics of ENS progenitors, and the developmental timing of neuronal and glial commitment. Summary StatementRet LoF affects proper development of the mouse ENS through multiple distinct cellular phenotypes including restriction of neuronal fate potential, disruption of ENCDC migration, and modulation of progenitor proliferation rate.

developmental biology↗

bioRxiv2018

Transcriptional suppression from KMT2D loss disrupts cell cycle and hypoxic responses in neurodevelopmental models of Kabuki syndrome

Chromatin modifiers act to coordinate gene expression changes critical to neuronal differentiation from neural stem/progenitor cells (NSPCs). Lysine-specific methyltransferase 2D (KMT2D) encodes a histone methyltransferase that promotes transcriptional activation, and is frequently mutated in cancers and in the majority (>70%) of patients diagnosed with the congenital, multisystem intellectual disability (ID) disorder Kabuki syndrome 1 (KS1). Critical roles for KMT2D are established in various non-neural tissues, but the effects of KMT2D loss in brain cell development have not been described. We conducted parallel studies of proliferation, differentiation, transcription, and chromatin profiling in KMT2D-deficient human and mouse models to define KMT2D-regulated functions in neurodevelopmental contexts, including adult-born hippocampal NSPCs in vivo and in vitro. We report cell-autonomous defects in proliferation, cell cycle, and survival, accompanied by early NSPC maturation in several KMT2D-deficient model systems. Transcriptional suppression in KMT2D-deficient cells indicated strong perturbation of hypoxia-responsive metabolism pathways. Functional experiments confirmed abnormalities of cellular hypoxia responses in KMT2D-deficient neural cells, and accelerated NSPC maturation in vivo. Together, our findings support a model in which loss of KMT2D function suppresses expression of oxygen-responsive gene programs important to neural progenitor maintenance, resulting in precocious neuronal differentiation in a mouse model of KS1.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC=\"FIGDIR/small/484410v3_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (22K):\norg.highwire.dtl.DTLVardef@55dd1aorg.highwire.dtl.DTLVardef@1270c80org.highwire.dtl.DTLVardef@a5bda2org.highwire.dtl.DTLVardef@144df37_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2017

Variation in neuronal activity state, axonal projection target, and position principally define the transcriptional identity of individual neocortical projection neurons.

Single-cell RNA sequencing technologies have generated the first catalogs of transcriptionally defined neuronal subtypes of the brain. However, the biologically informative cellular processes that contribute to neuronal subtype specification and transcriptional heterogeneity remain unclear. By comparing the gene expression profiles of single layer 6 corticothalamic neurons in somatosensory cortex, we show that transcriptional subtypes primarily reflect axonal projection pattern, laminar position within the cortex, and neuronal activity state. Pseudotemporal ordering of 1023 cellular responses to manipulation of sensory input demonstrates that changes in expression of activity-induced genes both reinforced cell-type identity and contributed to increased transcriptional heterogeneity within each cell type. This is due to cell-type specific biases in the choice of transcriptional states following manipulation of neuronal activity. These results reveal that axonal projection pattern, laminar position, and activity state define significant axes of variation that contribute both to the transcriptional identity of individual neurons and to the transcriptional heterogeneity within each neuronal subtype.

neuroscience↗

bioRxiv2017

Temporal and spatial variation among single dopaminergic neuron transcriptomes informs cellular phenotype diversity and Parkinson’s Disease gene prioritization

Parkinsons disease (PD) is caused by the collapse of substantia nigra (SN) dopaminergic (DA) neurons of the midbrain (MB), while other DA populations remain relatively intact. Common variation influencing susceptibility to sporadic PD has been primarily identified through genome wide association studies (GWAS). However, like many other common genetic diseases, the genes impacted by common PD-associated variation remain to be elucidated. Here, we used single-cell RNA-seq to characterize DA neuron populations in the mouse brain at embryonic and early postnatal timepoints. These data allow for the unbiased identification of DA neuron subpopulations, including a novel postnatal neuroblast population and SN DA neurons. Comparison of SN DA neurons with other DA neurons populations in the brain reveals a unique transcriptional profile, novel marker genes, and specific gene regulatory networks. By integrating these cell population specific data with published GWAS, we develop a scoring system for prioritizing candidate genes in PD-associated loci. With this, we prioritize candidate genes in all 32 GWAS intervals implicated in sporadic PD risk, the first such systematically generated list. From this we confirm that the prioritized candidate gene CPLX1 disrupts the nigrostriatal pathway when knocked out in mice. Ultimately, this systematic rationale leads to the identification of biologically pertinent candidates and testable hypotheses for sporadic PD that will inform a new era of PD genetic research.

genetics↗