Unveiling APOL1 haplotypes in a predominantly African-American cohort of kidney transplant patients: a novel classification using probe-independent quantitative real-time PCR.

Introduction: Apolipoprotein-L1 (APOL1) is a primate-specific protein component of high-density lipoprotein (HDL). Two variants of APOL1 (G1 and G2), provide resistance to parasitic infections in African Americans but are also implicated in kidney-related diseases and transplant outcomes in recipients. This study aims to identify these risk variants using a novel probe-independent quantitative real-time PCR method in a high African American recipient cohort.

Exogenous mitochondrial transfer increases energy expenditure and attenuates adiposity gains in mice with diet-induced obesity.

Obesity is associated with chronic multi-system bioenergetic stress that may be improved by increasing the number of healthy mitochondria available across organ systems. However, treatments capable of increasing mitochondrial content are generally limited to endurance exercise training paradigms, which are not always sustainable long-term, let alone feasible for many patients with obesity. Recent studies have shown that local transfer of exogenous mitochondria from healthy donor tissues can improve bioenergetic outcomes and alleviate the effects of tissue injury in recipients with organ specific disease.

Unveiling APOL1 Haplotypes: A Novel Classification Through Probe-Independent Quantitative Real-Time PCR.

Introduction: Apolipoprotein-L1 (APOL1) is a primate-specific protein component of high- density lipoprotein (HDL). Two variants of APOL1 (G1 and G2), provide resistance to parasitic infections in African Americans but are also implicated in kidney-related diseases and transplant outcomes in recipients. This study aims to identify these risk variants using a novel probe- independent quantitative real-time PCR method in a high African American recipient cohort.

Circulating microRNA Profiles for Premature Cardiovascular Death in Patients with Kidney Failure with Replacement Therapy.

Introduction: Patients with kidney failure with replacement therapy (KFRT) suffer from a disproportionately high cardiovascular disease burden. Circulating small non-coding RNAs (c-sncRNAs) have emerged as novel epigenetic regulators and are suggested as novel biomarkers and therapeutic targets for cardiovascular disease; however, little is known about the associations of c-sncRNAs with premature cardiovascular death in KFRT.

Methods: In a pilot case-control study of 50 hemodialysis patients who died of cardiovascular events as cases, and 50 matched hemodialysis controls who remained alive during a median follow-up of 2.

Single-cell RNA sequencing reveals peripheral blood mononuclear immune cell landscape associated with operational tolerance in a kidney transplant recipient.

Operational tolerance (OT) after kidney transplantation is defined as stable graft acceptance without the need for immunosuppression therapy. However, it is not clear which cellular and molecular pathways are driving tolerance in these patients. In this first-of-its-kind pilot study, we assessed the immune landscape associated with OT using single-cell analyses.

Single nuclei transcriptomics delineates complex immune and kidney cell interactions contributing to kidney allograft fibrosis.

Chronic allograft dysfunction (CAD), characterized histologically by interstitial fibrosis and tubular atrophy, is the major cause of kidney allograft loss. Here, using single nuclei RNA sequencing and transcriptome analysis, we identified the origin, functional heterogeneity, and regulation of fibrosis-forming cells in kidney allografts with CAD. A robust technique was used to isolate individual nuclei from kidney allograft biopsies and successfully profiled 23,980 nuclei from five kidney transplant recipients with CAD and 17,913 nuclei from three patients with normal allograft function.

Key hepatoprotective roles of mitochondria in liver regeneration.

Treatment of advanced liver disease using surgical modalities is possible due to the liver's innate ability to regenerate following resection. Several key cellular events in the regenerative process converge at the mitochondria, implicating their crucial roles in liver regeneration. Mitochondria enable the regenerating liver to meet massive metabolic demands by coordinating energy production to drive cellular proliferative processes and vital homeostatic functions.

Mitochondrial Role in Oncogenesis and Potential Chemotherapeutic Strategy of Mitochondrial Infusion in Breast Cancer.

Triple negative breast cancer (TNBC) is one of the most aggressive cancers diagnosed amongst women with a high rate of treatment failure and a poor prognosis. Mitochondria have been found to be key players in oncogenesis and tumor progression by mechanisms such as altered metabolism, reactive oxygen species (ROS) production and evasion of apoptosis. Therefore, mitochondrial infusion is an area of interest for cancer treatment.

A Review of Defatting Strategies for Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease is a huge cause of chronic liver failure around the world. This condition has become more prevalent as rates of metabolic syndrome, type 2 diabetes, and obesity have also escalated. The unfortunate outcome for many people is liver cirrhosis that warrants transplantation or being unable to receive a transplant since many livers are discarded due to high levels of steatosis.

Tip60 acetylation of histone H3K4 temporally controls chromosome passenger complex localization.

The Chromosome Passenger Complex (CPC) generates chromosome autonomous signals that regulate mitotic events critical for genome stability. Tip60 is a lysine acetyltransferase that is a tumor suppressor and is targeted for proteasomal degradation by oncogenic papilloma viruses. Mitotic regulation requires the localization of the CPC to inner centromeres, which is driven by the Haspin kinase phosphorylating histone H3 on threonine 3 (H3T3ph).

ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival.

MicroRNAs: Novel Targets in Hepatic Ischemia-Reperfusion Injury.

Hepatic ischemia-reperfusion injury (IRI) is one of the main factors for early allograft dysfunction (EAD), which may lead to graft rejection, graft loss, or shortened graft life in liver transplantation. Hepatic IRI appears to be inevitable during the majority of liver procurement and transportation of donor organs, resulting in a cascade of biological changes. The activation of signaling pathways during IRI results in the up- and downregulation of genes and microRNAs (miRNAs).

Integrative Analyses of Circulating Small RNAs and Kidney Graft Transcriptome in Transplant Glomerulopathy.

Transplant glomerulopathy develops through multiple mechanisms, including donor-specific antibodies, T cells and innate immunity. This study investigates circulating small RNA profiles in serum samples of kidney transplant recipients with biopsy-proven transplant glomerulopathy. Among total small RNA population, miRNAs were the most abundant species in the serum of kidney transplant patients.

A Functional Variant on 9p21.3 Related to Glioma Risk Affects Enhancer Activity and Modulates Expression of CDKN2B-AS1.

Genome-wide association studies have identified SNPs associated with glioma risk on 9p21.3, but biological mechanisms underlying this association are unknown. We tested the hypothesis that a functional SNP on 9p21.

Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury.

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI).

Technical advancements in epigenomics and applications in transplantation.

Purpose Of Review: To summarize recently developed next generation sequencing-based methods to study epigenomics and epitranscriptomics. To elucidate the potential applications of these recently developed methods in transplantation research.

Recent Findings: There are several methods established with the collaborative efforts from different consortiums, such as ENCODE, Human Cell Atlas, and exRNA consortium to study role of epigenetics in human health.

A functional variant on 20q13.33 related to glioma risk alters enhancer activity and modulates expression of multiple genes.

Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with glioma risk on 20q13.33, but the biological mechanisms underlying this association are unknown. We tested the hypothesis that a functional SNP on 20q13.

Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat. Due to the asymptomatic nature of the disease and lack of curative treatment modalities, the 5-y survival rate of PDAC patients is one of the lowest of any cancer type. The recurrent genetic alterations in PDAC are yet to be targeted.

FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury.

Dendritic cells (DCs) are central in regulating immune responses of kidney ischemia-reperfusion injury (IRI), and strategies to alter DC function may provide new therapeutic opportunities. Sphingosine 1-phosphate (S1P) modulates immunity through binding to its receptors (S1P1-5), and protection from kidney IRI occurs in mice treated with S1PR agonist, FTY720 (FTY). We tested if propagation of DCs with FTY could be used as cellular therapy to limit the off-target effects associated with systemic FTY administration in kidney IRI.

Applications of CRISPR technologies in transplantation.

In transplantation, the ever-increasing number of an organ's demand and long-term graft dysfunction constitute some of the major problems. Therefore, alternative solutions to increase the quantity and quality of the organ supply for transplantation are desired. On this subject, revolutionary Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology holds enormous potential for the scientific community with its expanding toolbox.

CEMIP upregulates BiP to promote breast cancer cell survival in hypoxia.

Cell migration-inducing protein (CEMIP) and binding immunoglobulin protein (BiP) are upregulated in human cancers, where they drive cancer progression and metastasis. It has been shown that CEMIP resides in the endoplasmic reticulum (ER) where it interacts with BiP to induce cell migration, but the relationship between the two proteins was previously unknown. Here we show that CEMIP mediates activation of the BiP promoter and upregulates BiP transcript and protein levels in breast cancer cell lines.

Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer.

Background: The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events.

Results: We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites.

CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response.

Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment.

Temporal and Spatial Epigenome Editing Allows Precise Gene Regulation in Mammalian Cells.

Cell-type specific gene expression programs are tightly linked to epigenetic modifications on DNA and histone proteins. Here, we used a novel CRISPR-based epigenome editing approach to control gene expression spatially and temporally. We show that targeting dCas9-p300 complex to distal non-regulatory genomic regions reprograms the chromatin state of these regions into enhancer-like elements.