Mouse genome-wide association studies and systems genetics uncover the genetic architecture associated with hepatic pharmacokinetic and pharmacodynamic properties of a constrained ethyl antisense oligonucleotide targeting Malat1

Pirie, Elaine; Ray, Shayoni; Pan, Calvin; Fu, Wuxia; Powers, Andrew F.; Polikoff, Danielle; Miller, Colton M.; Kudrna, Katrina M.; Harris, Edward N.; Lusis, Aldons J.; Crooke, Rosanne M.; Lee, Richard G.

doi:10.1371/journal.pgen.1007732

Cited by 7 publications

(6 citation statements)

References 63 publications

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“…The length of human MALAT1 reached about 8.7 knt and mouse RNA was shorter (~6.7knt) than human RNA [ 29 ]. MALAT1 was one of earlier investigated long noncoding RNAs in tumor and other fields [ 8 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic and immunological significance of metastasis associated lung adenocarcinoma transcript 1 among different kinds of cancers

et al. 2021

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LncRNAs belong to the type of noncoding RNA transcripts, which exceed 200 nucleotides in size. MALAT1 as one of the earlier identified lncRNAs in cancer is investigated by more and more scientific researchers. Expression, clinical significance and function of MALAT1 in pan-cancer exist as big difference. To detect the expression and clinical significance of MALAT1 gene precisely and comprehensively among different kinds of cancers, some classical databases such as GEPIA, TIMER, KM Plotter, and PrognoScan were fully applied. An immunological role of MALAT1 among different kinds of cancers was also determined in TIMER database. Our results showed that MALAT1 was differently expressed in different kinds of cancers using GEPIA, Oncomine, and TIMER databases to analyze. Especially, MALAT1 high RNA level was related to the early stage in lung and gastric cancer patients. MALAT1 expression was closely related to prognosis among different cancer patients. Furthermore, expression of MALAT1 was related to tumor immune cell infiltrating. Expression level of MALAT1 was also related to immune makers such as macrophage, T cell, NK cells, and so on. These findings indicate that MALAT1 could be a potential prognostic biomarker of some kinds of cancer and was significantly correlated with tumor-infiltrating immune cells in a wide variety of cancers.

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Section: Discussionmentioning

confidence: 99%

Prognostic and immunological significance of metastasis associated lung adenocarcinoma transcript 1 among different kinds of cancers

et al. 2021

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“…18 It is also involved in antisense oligonucleotide pharmacokinetics and nanoparticle uptake, and it controls Von Willebrandt factor-factor VIII complex half-life and immunogenicity. [19][20][21] Both Stabilins can bind acetylated LDL, oxidized LDL (oxLDL), advanced glycation end products, and collagen propeptides. 22,23 Because of their ligand profiles, including acetylated LDL and oxLDL, which are known to alter macrophage responses in atherosclerosis, 24,25 it can be hypothesized that Stab1 and Stab2 may be involved in atherosclerosis.…”

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confidence: 99%

Targeting of Scavenger Receptors Stabilin-1 and Stabilin-2 Ameliorates Atherosclerosis by a Plasma Proteome Switch Mediating Monocyte/Macrophage Suppression

et al. 2022

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BACKGROUND: Scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are preferentially expressed by liver sinusoidal endothelial cells. They mediate the clearance of circulating plasma molecules controlling distant organ homeostasis. Studies suggest that Stab1 and Stab2 may affect atherosclerosis. Although subsets of tissue macrophages also express Stab1, hematopoietic Stab1 deficiency does not modulate atherogenesis. Here, we comprehensively studied how targeting Stab1 and Stab2 affects atherosclerosis. METHODS: ApoE-KO mice were interbred with Stab1-KO and Stab2-KO mice and fed a Western diet. For antibody targeting, Ldlr-KO mice were also used. Unbiased plasma proteomics were performed and independently confirmed. Ligand binding studies comprised glutathione-S-transferase–pulldown and endocytosis assays. Plasma proteome effects on monocytes were studied by single-cell RNA sequencing in vivo, and by gene expression analyses of Stabilin ligand–stimulated and plasma-stimulated bone marrow–derived monocytes/macrophages in vitro. RESULTS: Spontaneous and Western diet–associated atherogenesis was significantly reduced in ApoE-Stab1-KO and ApoE-Stab2-KO mice. Similarly, inhibition of Stab1 or Stab2 by monoclonal antibodies significantly reduced Western diet–associated atherosclerosis in ApoE-KO and Ldlr-KO mice. Although neither plasma lipid levels nor circulating immune cell numbers were decisively altered, plasma proteomics revealed a switch in the plasma proteome, consisting of 231 dysregulated proteins comparing wildtype with Stab1/2-single and Stab1/2-double KO, and of 41 proteins comparing ApoE-, ApoE-Stab1-, and ApoE-Stab2-KO. Among this broad spectrum of common, but also disparate scavenger receptor ligand candidates, periostin, reelin, and TGFBi (transforming growth factor, β-induced), known to modulate atherosclerosis, were independently confirmed as novel circulating ligands of Stab1/2. Single-cell RNA sequencing of circulating myeloid cells of ApoE-, ApoE-Stab1-, and ApoE-Stab2-KO mice showed transcriptomic alterations in patrolling (Ccr2 – /Cx3cr1 ++ /Ly6C lo ) and inflammatory (Ccr2 + /Cx3cr1 + /Ly6C hi ) monocytes, including downregulation of proatherogenic transcription factor Egr1. In wildtype bone marrow–derived monocytes/macrophages, ligand exposure alone did not alter Egr1 expression in vitro. However, exposure to plasma from ApoE-Stab1-KO and ApoE-Stab2-KO mice showed a reverted proatherogenic macrophage activation compared with ApoE-KO plasma, including downregulation of Egr1 in vitro. CONCLUSIONS: Inhibition of Stab1/Stab2 mediates an anti-inflammatory switch in the plasma proteome, including direct Stabilin ligands. The altered plasma proteome suppresses both patrolling and inflammatory monocytes and, thus, systemically protects against atherogenesis. Altogether, anti-Stab1– and anti-Stab2–targeted therapies provide a novel approach for the future treatment of atherosclerosis.

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“…Pirie and colleagues 89 have recently used systems genetics to examine the pharmacokinetics and pharmacodynamics of antisense oligonucleotides (ASOs), which can be used to modify the expression of genes in vivo and have become widely used therapeutic agents. ASOs exhibit variation in efficacy in patient populations, and the authors have used transcriptomic analysis and genome-wide association in the HMDP mouse population to identify several genes associated with the uptake and potency of ASOs.…”

Section: Genetic Interactionsmentioning

confidence: 99%

Systems genetics applications in metabolism research

2019

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The common forms of metabolic diseases are highly complex, involving hundreds of genes, environmental and lifestyle factors, age-related changes, sex differences and gut-microbiome interactions. Systems genetics is a population-based approach to address this complexity. In contrast to commonly used 'reductionist' approaches, such as gain or loss of function, that examine one element at a time, systems genetics uses high-throughput 'omics' technologies to quantitatively assess the many molecular differences among individuals in a population and then to relate these to physiologic functions or disease states. Unlike genome-wide association studies, systems genetics seeks to go beyond the identification of disease-causing genes to understand higher-order interactions at the molecular level. The purpose of this review is to introduce the systems genetics applications in the areas of metabolic and cardiovascular disease. Here, we explain how large clinical and omics-level data and databases from both human and animal populations are available to help researchers place genes in the context of pathways and networks and formulate hypotheses that can then be experimentally examined. We provide lists of such databases and examples of the integration of reductionist and systems genetics data. Among the important applications emerging is the development of improved nutritional and pharmacological strategies to address the rise of metabolic diseases.

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Mouse genome-wide association studies and systems genetics uncover the genetic architecture associated with hepatic pharmacokinetic and pharmacodynamic properties of a constrained ethyl antisense oligonucleotide targeting Malat1

Cited by 7 publications

References 63 publications

Prognostic and immunological significance of metastasis associated lung adenocarcinoma transcript 1 among different kinds of cancers

Prognostic and immunological significance of metastasis associated lung adenocarcinoma transcript 1 among different kinds of cancers

Targeting of Scavenger Receptors Stabilin-1 and Stabilin-2 Ameliorates Atherosclerosis by a Plasma Proteome Switch Mediating Monocyte/Macrophage Suppression

Systems genetics applications in metabolism research

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