Systematic elucidation of genetic mechanisms underlying cholesterol uptake

Hamilton, Marisa C; Fife, James D.; Akinci, Ersin; Yu, Tian; Khowpinitchai, Benyapa; Cha, Minsun; Barkal, Sammy; Thi, Thi Tun; Yeo, Grace H.T.; Barroso, Juan Pablo Ramos; Francoeur, Matthew Jake; Velimirovic, Minja; Gifford, David K.; Lettre, Guillaume; Yu, Haojie; Cassa, Christopher A.; Sherwood, Richard I.

doi:10.1016/j.xgen.2023.100304

Cited by 4 publications

(1 citation statement)

References 119 publications

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“…These strategies are also taken into consideration for the development of new drugs for several disorders which are closely related to the occurrence of cardiovascular diseases. Often, the focus of such research is on the genetic causes of lipid disorders, which is understandable considering the role lipids have in the development of CVDs [ 32 ]. For instance, the gene for PCSK9 (proprotein convertase subtilisin kexin 9), whose specific variants cause familial hypercholesterolemia (FH), as well as its variants lead to striking decreases in low-density lipoprotein cholesterol (LDL-C) and to atherosclerosis risk [ 33 ].…”

Section: Molecular Biology As a Promoter Of Research And Treatment Of...mentioning

confidence: 99%

DNA and RNA Molecules as a Foundation of Therapy Strategies for Treatment of Cardiovascular Diseases

Rakićević

2023

Pharmaceutics

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There has always been a tendency of medicine to take an individualised approach to treating patients, but the most significant advances were achieved through the methods of molecular biology, where the nucleic acids are in the limelight. Decades of research of molecular biology resulted in setting medicine on a completely new platform. The most significant current research is related to the possibilities that DNA and RNA analyses can offer in terms of more precise diagnostics and more subtle stratification of patients in order to identify patients for specific therapy treatments. Additionally, principles of structure and functioning of nucleic acids have become a motive for creating entirely new therapy strategies and an innovative generation of drugs. All this also applies to cardiovascular diseases (CVDs) which are the leading cause of mortality in developed countries. This review considers the most up-to-date achievements related to the use of translatory potential of DNA and RNA in treatment of cardiovascular diseases, and considers the challenges and prospects in this field. The foundations which allow the use of translatory potential are also presented. The first part of this review focuses on the potential of the DNA variants which impact conventional therapies and on the DNA variants which are starting points for designing new pharmacotherapeutics. The second part of this review considers the translatory potential of non-coding RNA molecules which can be used to formulate new generations of therapeutics for CVDs.

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Section: Molecular Biology As a Promoter Of Research And Treatment Of...mentioning

confidence: 99%

DNA and RNA Molecules as a Foundation of Therapy Strategies for Treatment of Cardiovascular Diseases

Rakićević

2023

Pharmaceutics

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RABIF promotes hepatocellular carcinoma progression through regulation of mitophagy and glycolysis

Feng,

Zhang,

Wen

et al. 2024

Commun Biol

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The RAB interacting factor (RABIF) is a putative guanine nucleotide exchange factor that also functions as a RAB-stabilizing holdase chaperone. It has been implicated in pathogenesis of several cancers. However, the functional role and molecular mechanism of RABIF in hepatocellular carcinoma (HCC) are not entirely known. Here, we demonstrate an upregulation of RABIF in patients with HCC, correlating with a poor prognosis. RABIF inhibition results in decreased HCC cell growth both in vitro and in vivo. Our study reveals that depleting RABIF attenuates the STOML2-PARL-PGAM5 axis-mediated mitophagy. Consequently, this reduction in mitophagy results in diminished mitochondrial reactive oxygen species (mitoROS) production, thereby alleviating the HIF1α-mediated downregulation of glycolytic genes HK1, HKDC1, and LDHB. Additionally, we illustrate that RABIF regulates glucose uptake by controlling RAB10 expression. Importantly, the knockout of RABIF or blockade of mitophagy sensitizes HCC cells to sorafenib. This study uncovers a previously unrecognized role of RABIF crucial for HCC growth and identifies it as a potential therapeutic target.

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Joint genotypic and phenotypic outcome modeling improves base editing variant effect quantification

Ryu,

Barkal,

et al. 2023

Preprint

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CRISPR base editing screens are powerful tools for studying disease-associated variants at scale. However, the efficiency and precision of base editing perturbations vary, confounding the assessment of variant-induced phenotypic effects. Here, we provide an integrated pipeline that improves the estimation of variant impact in base editing screens. We perform high-throughput ABE8e-SpRY base editing screens with an integrated reporter construct to measure the editing efficiency and outcomes of each gRNA alongside their phenotypic consequences. We introduce BEAN, a Bayesian network that accounts for per-guide editing outcomes and target site chromatin accessibility to estimate variant impacts. We show this pipeline attains superior performance compared to existing tools in variant classification and effect size quantification. We use BEAN to pinpoint common variants that alter LDL uptake, implicating novel genes. Additionally, through saturation base editing ofLDLR, we enable accurate quantitative prediction of the effects of missense variants on LDL-C levels, which aligns with measurements in UK Biobank individuals, and identify structural mechanisms underlying variant pathogenicity. This work provides a widely applicable approach to improve the power of base editor screens for disease-associated variant characterization.

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Systematic elucidation of genetic mechanisms underlying cholesterol uptake

Cited by 4 publications

References 119 publications

DNA and RNA Molecules as a Foundation of Therapy Strategies for Treatment of Cardiovascular Diseases

DNA and RNA Molecules as a Foundation of Therapy Strategies for Treatment of Cardiovascular Diseases

RABIF promotes hepatocellular carcinoma progression through regulation of mitophagy and glycolysis

Joint genotypic and phenotypic outcome modeling improves base editing variant effect quantification

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