A genome-wide spectrum of tandem repeat expansions in 338,963 humans.

The Genome Aggregation Database (gnomAD), widely recognized as the gold-standard reference map of human genetic variation, has largely overlooked tandem repeat (TR) expansions, despite the fact that TRs constitute ∼6% of our genome and are linked to over 50 human diseases. Here, we introduce the TR-gnomAD (https://wlcb.oit.uci.edu/TRgnomAD), a biobank-scale reference of 0.86 million TRs derived from 338,963 whole-genome sequencing (WGS) samples of diverse ancestries (39.5% non-European samples). TR-gnomAD offers critical insights into ancestry-specific disease prevalence using disparities in TR unit number frequencies among ancestries. Moreover, TR-gnomAD is able to differentiate between common, presumably benign TR expansions, which are prevalent in TR-gnomAD, from those potentially pathogenic TR expansions, which are found more frequently in disease groups than within TR-gnomAD. Together, TR-gnomAD is an invaluable resource for researchers and physicians to interpret TR expansions in individuals with genetic diseases.

A PPARγ/long noncoding RNA axis regulates adipose thermoneutral remodeling in mice.

Interplay between energy-storing white adipose cells and thermogenic beige adipocytes contributes to obesity and insulin resistance. Irrespective of specialized niche, adipocytes require the activity of the nuclear receptor PPARγ for proper function. Exposure to cold or adrenergic signaling enriches thermogenic cells though multiple pathways that act synergistically with PPARγ; however, the molecular mechanisms by which PPARγ licenses white adipose tissue to preferentially adopt a thermogenic or white adipose fate in response to dietary cues or thermoneutral conditions are not fully elucidated. Here, we show that a PPARγ/long noncoding RNA (lncRNA) axis integrates canonical and noncanonical thermogenesis to restrain white adipose tissue heat dissipation during thermoneutrality and diet-induced obesity. Pharmacologic inhibition or genetic deletion of the lncRNA Lexis enhances uncoupling protein 1-dependent (UCP1-dependent) and -independent thermogenesis. Adipose-specific deletion of Lexis counteracted diet-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. Single-nuclei transcriptomics revealed that Lexis regulates a distinct population of thermogenic adipocytes. We systematically map Lexis motif preferences and show that it regulates the thermogenic program through the activity of the metabolic GWAS gene and WNT modulator TCF7L2. Collectively, our studies uncover a new mode of crosstalk between PPARγ and WNT that preserves white adipose tissue plasticity.

Endothelial cells LEENE on noncoding RNAs in diabetic vasculopathy.

Long noncoding RNAs (lncRNAs) have emerged as key mediators of regulated gene expression in diverse biologic contexts, including cardiovascular disease. In this issue of the JCI, Tang, Luo, and colleagues explored the contributions of lncRNAs in diabetic vasculopathy. The authors identified the lncRNA LEENE as a key mediator of angiogenesis and ischemic response. In a model of diabetic peripheral arterial disease, loss of LEENE led to impaired vascular perfusion, while its overexpression rescued the ischemic defect. The authors used unbiased chromatin affinity assays to decipher LEENE's interactome and mode of action. These findings offer insights as to why patients with diabetes are uniquely susceptible to developing peripheral vascular disease and fill important gaps in our understanding of mechanisms that connect metabolic dysregulation with impaired angiogenesis.

Pharmacotherapy in familial hypercholesterolemia - Current state and emerging paradigms.

Familial hypercholesterolemia is a highly prevalent but underdiagnosed disease marked by increased risk of cardiovascular morbidity and mortality. Aggressive reduction of LDL-cholesterol is a hallmark of cardiovascular risk mitigation in familial hypercholesterolemia. More recently, we have witnessed an expanded repertoire of pharmacologic agents that directly target LDL-cholesterol and/or reduce heart disease burden. In this state-of-the-art review, we explore the development, clinical efficacy and limitations of existing and potential future therapeutics in familial hypercholesterolemia.

Cancer therapy's impact on lipid metabolism: Mechanisms and future avenues.

Atherosclerotic cardiovascular disease is a growing threat among cancer patients. Not surprisingly, cancer-targeting therapies have been linked to metabolic dysregulation including changes in local and systemic lipid metabolism. Thus, tumor development and cancer therapeutics are intimately linked to cholesterol metabolism and may be a driver of increased cardiovascular morbidity and mortality in this population. Chemotherapeutic agents affect lipid metabolism through diverse mechanisms. In this review, we highlight the mechanistic and clinical evidence linking commonly used cytotoxic therapies with cholesterol metabolism and potential opportunities to limit atherosclerotic risk in this patient population. Better understanding of the link between atherosclerosis, cancer therapy, and cholesterol metabolism may inform optimal lipid therapy for cancer patients and mitigate cardiovascular disease burden.

Immune Checkpoint Therapies and Atherosclerosis: Mechanisms and Clinical Implications: JACC State-of-the-Art Review.

Immune checkpoint inhibitor therapy has revolutionized the treatment of advanced malignancies in recent years. Numerous reports have detailed the myriad of possible adverse inflammatory effects of immune checkpoint therapies, including within the cardiovascular system. However, these reports have been largely limited to myocarditis. The critical role of inflammation and adaptive immunity in atherosclerosis has been well characterized in preclinical studies, and several emerging clinical studies indicate a potential role of immune checkpoint targeting therapies in the development and exacerbation of atherosclerosis. In this review, we provide an overview of the role of T-cell immunity in atherogenesis and describe the molecular effects and clinical associations of both approved and investigational immune checkpoint therapy on atherosclerosis. We also highlight the role of cholesterol metabolism in oncogenesis and discuss the implications of these associations on future treatment and monitoring of atherosclerotic cardiovascular disease in the oncologic population receiving immune checkpoint therapy.

Crosstalk between epitranscriptomic and epigenetic mechanisms in gene regulation.

Epigenetic modifications occur on genomic DNA and histones to influence gene expression. More recently, the discovery that mRNA undergoes similar chemical modifications that powerfully impact transcript turnover and translation adds another layer of dynamic gene regulation. Central to precise and synchronized regulation of gene expression is intricate crosstalk between multiple checkpoints involved in transcript biosynthesis and processing. There are more than 100 internal modifications of RNA in mammalian cells. The most common is N6-methyladenosine (m6A) methylation. Although m6A is established to influence RNA stability dynamics and translation efficiency, rapidly accumulating evidence shows significant crosstalk between RNA methylation and histone/DNA epigenetic mechanisms. These interactions specify transcriptional outputs, translation, recruitment of chromatin modifiers, as well as the deployment of the m6A methyltransferase complex (MTC) at target sites. In this review, we dissect m6A-orchestrated feedback circuits that regulate histone modifications and the activity of regulatory RNAs, such as long noncoding (lnc)RNA and chromosome-associated regulatory RNA. Collectively, this body of evidence suggests that m6A acts as a versatile checkpoint that can couple different layers of gene regulation with one another.

DDX17 is an essential mediator of sterile NLRC4 inflammasome activation by retrotransposon RNAs.

Detection of microbial products by multiprotein complexes known as inflammasomes is pivotal to host defense against pathogens. Nucleotide-binding domain leucine-rich repeat (NLR) CARD domain containing 4 (NLRC4) forms an inflammasome in response to bacterial products; this requires their detection by NLR family apoptosis inhibitory proteins (NAIPs), with which NLRC4 physically associates. However, the mechanisms underlying sterile NLRC4 inflammasome activation, which is implicated in chronic noninfectious diseases, remain unknown. Here, we report that endogenous short interspersed nuclear element (SINE) RNAs, which promote atrophic macular degeneration (AMD) and systemic lupus erythematosus (SLE), induce NLRC4 inflammasome activation independent of NAIPs. We identify DDX17, a DExD/H box RNA helicase, as the sensor of SINE RNAs that licenses assembly of an inflammasome comprising NLRC4, NLR pyrin domain­containing protein 3, and apoptosis-associated speck-like protein­containing CARD and induces caspase-1 activation and cytokine release. Inhibiting DDX17-mediated NLRC4 inflammasome activation decreased interleukin-18 release in peripheral blood mononuclear cells of patients with SLE and prevented retinal degeneration in an animal model of AMD. Our findings uncover a previously unrecognized noncanonical NLRC4 inflammasome activated by endogenous retrotransposons and provide potential therapeutic targets for SINE RNA­driven diseases.

Transcriptional regulation of N6-methyladenosine orchestrates sex-dimorphic metabolic traits.

Males and females exhibit striking differences in the prevalence of metabolic traits including hepatic steatosis, a key driver of cardiometabolic morbidity and mortality. RNA methylation is a widespread regulatory mechanism of transcript turnover. Here, we show that presence of the RNA modification N6-methyladenosine (m6A) triages lipogenic transcripts for degradation and guards against hepatic triglyceride accumulation. In male but not female mice, this protective checkpoint stalls under lipid-rich conditions. Loss of m6A control in male livers increases hepatic triglyceride stores, leading to a more 'feminized' hepatic lipid composition. Crucially, liver-specific deletion of the m6A complex protein Mettl14 from male and female mice significantly diminishes sex-specific differences in steatosis. We further surmise that the m6A installing machinery is subject to transcriptional control by the sex-responsive BCL6-STAT5 axis in response to dietary conditions. These data show that m6A is essential for precise and synchronized control of lipogenic enzyme activity and provide insights into the molecular basis for the existence of sex-specific differences in hepatic lipid traits.

Changes in lipid composition associated with electronic cigarette use.

BACKGROUND: Electronic cigarette use is on the rise despite a number of reports linking electronic cigarettes with adverse health outcomes. Recent studies have suggested that alterations in lipid signaling may be one mechanism by which electronic cigarettes contribute to lung pulmonary function. Vitamin E acetate, for example, is synthetic form of Vitamin E transported via lipids, found to be associated with electronic cigarette associated lung injury. Lipids are absolutely critical for normal lung physiology and perturbations in a number of lipid pathways have been associated with respiratory illness. Is it conceivable that electronic cigarette use even in seemingly healthy cohorts are associated with alterations in lipid pathways? METHODS: To investigate quantitative alterations in the plasma lipidome associated with electronic cigarette use in healthy we obtained plasma samples from 119 male and female participants with who were either: (1) chronic tobacco cigarette (TC) smokers (> 12 months of self-reported TC use), (2) chronic Electronic cigarette (EC) users (> 12 months of self-reported EC use), or (3) non-users. We measured quantitative lipid species across different lipid sub-classes from plasma samples using the Sciex Lipidyzer. RESULTS: We found that male and female tobacco and electronic cigarette users had distinct lipidome signatures across a number of lipid species although the vast majority of lipids were unchanged when compared to non-users. Intriguingly, we found that female but not male electronic cigarette users had lower levels of plasmalogens, critical glycerophospholipids secreted by alveoli and required for normal surfactant function. CONCLUSIONS: In summary, our study does not reveal striking changes associated with electronic cigarette use but we observed sex-specific changes in lipids known to be critical for lung function.

Collaborative interactions of heterogenous ribonucleoproteins contribute to transcriptional regulation of sterol metabolism in mice.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are a group of functionally versatile proteins that play critical roles in the biogenesis, cellular localization and transport of RNA. Here, we outline a role for hnRNPs in gene regulatory circuits controlling sterol homeostasis. Specifically, we find that tissue-selective loss of the conserved hnRNP RALY enriches for metabolic pathways. Liver-specific deletion of RALY alters hepatic lipid content and serum cholesterol level. In vivo interrogation of chromatin architecture and genome-wide RALY-binding pattern reveal insights into its cooperative interactions and mode of action in regulating cholesterogenesis. Interestingly, we find that RALY binds the promoter region of the master metabolic regulator Srebp2 and show that it directly interacts with coactivator Nuclear Transcription Factor Y (NFY) to influence cholesterogenic gene expression. Our work offers insights into mechanisms orchestrating selective promoter activation in metabolic control and a model by which hnRNPs can impact health and disease states.

Immune Biomarkers in the Prediction of Future Myocardial Infarctions in People With Human Immunodeficiency Virus.

In a retrospective case control analysis, following adjustments for high-sensitivity C-reactive protein (hsCRP), traditional cardiovascular risk factors, and the CD4/CD8 T-cell ratio, higher lipopolysaccharide-binding protein (LBP) was associated with future myocardial infarctions in hsCRP human immunodeficiency virus (HIV). LBP may be a marker of cardiovascular risk with utility in HIV.

Cardiac TRPV1 afferent signaling promotes arrhythmogenic ventricular remodeling after myocardial infarction.

Chronic sympathoexcitation is implicated in ventricular arrhythmogenesis (VAs) following myocardial infarction (MI), but the critical neural pathways involved are not well understood. Cardiac adrenergic function is partly regulated by sympathetic afferent reflexes, transduced by spinal afferent fibers expressing the transient receptor potential cation subfamily V member 1 (TRPV1) channel. The role of chronic TRPV1 afferent signaling in VAs is not known. We hypothesized that persistent TRPV1 afferent neurotransmission promotes VAs after MI. Using epicardial resiniferatoxin (RTX) to deplete cardiac TRPV1-expressing fibers, we dissected the role of this neural circuit in VAs after chronic MI in a porcine model. We examined the underlying mechanisms using molecular approaches, IHC, in vitro and in vivo cardiac electrophysiology, and simultaneous cardioneural mapping. Epicardial RTX depleted cardiac TRPV1 afferent fibers and abolished functional responses to TRPV1 agonists. Ventricular tachycardia/fibrillation (VT/VF) was readily inducible in MI subjects by programmed electrical stimulation or cesium chloride administration; however, TRPV1 afferent depletion prevented VT/VF induced by either method. Mechanistically, TRPV1 afferent depletion did not alter cardiomyocyte action potentials and calcium transients, the expression of ion channels, or calcium handling proteins. However, it attenuated fibrosis and mitigated electrical instability in the scar border zone. In vivo recordings of cardiovascular-related stellate ganglion neurons (SGNs) revealed that MI enhances SGN function and disrupts integrated neural processing. Depleting TRPV1 afferents normalized these processes. Taken together, these data indicate that, after MI, TRPV1 afferent-induced adrenergic dysfunction promotes fibrosis and adverse cardiac remodeling, and it worsens border zone electrical heterogeneity, resulting in electrically unstable ventricular myocardium. We propose targeting TRPV1-expressing afferent to reduce VT/VF following MI.