Biology subjects

Ijaz, L.

Publications and source records attributed to Ijaz, L..

3 recordsLinked to original sources

bioRxiv2023

MicroRNA-541-3p alters lipoproteins to reduce atherosclerosis by degrading Znf101 and Casz1 transcription factors

High apoB-containing low-density lipoproteins (LDL) and low apoA1-containing high-density lipoproteins (HDL) are associated with atherosclerosis. In search of a molecular regulator that could simultaneously and reciprocally control both LDL and HDL levels, we screened a microRNA (miR) library using human hepatoma Huh-7 cells. We identified miR-541-3p that both decreases apoB and increases apoA1 expression by inducing mRNA degradation of two different transcription factors, Znf101 and Casz1. Znf101 enhances apoB expression while Casz1 represses apoA1 expression. The hepatic knockdown of orthologous Zfp961 and Casz1 genes in mice altered plasma lipoproteins and reduced atherosclerosis without causing hepatic lipid accumulation, most likely by lowering hepatic triglyceride production, increasing HDL cholesterol efflux capacity, and reducing lipogenesis. Notably, human genetic variants in the MIR541, ZNF101, and CASZ1 loci are significantly associated with plasma lipids and lipoprotein levels. This study identifies miR-541-3p and Znf101/Casz1 as potential therapeutic agent and targets, respectively, to reduce plasma lipoproteins and atherosclerosis without causing liver steatosis. O_FIG O_LINKSMALLFIG WIDTH=153 HEIGHT=200 SRC="FIGDIR/small/565110v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@741dd1org.highwire.dtl.DTLVardef@151ad9aorg.highwire.dtl.DTLVardef@15c96a9org.highwire.dtl.DTLVardef@1a73b2d_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract. A schematic diagram depicting the role of miR-541-3p in the control of plasma lipoproteins and atherosclerosis.Our data show that miR-541-3p downregulates ZNF101 and CASZ1 by enhancing post-transcriptional degradation of mRNAs after interacting with their 3'-UTRs. Furthermore, our data indicate that ZNF101 is an enhancer of APOB, and CASZ1 is a repressor of APOA1. Hepatic knockdown (KD) of Zfp961, an orthologue of ZNF101, reduces plasma apoB-containing lipoproteins, whereas KD of Casz1 increases high density lipoproteins in mice. Furthermore, we show that hepatic KDs of these transcription factors reduces atherosclerosis in mice induced by the expression of mutant PCSK9. C_FIG

physiology↗

bioRxiv2023

Sex Chromosomes and Gonads Shape the Sex-Biased Transcriptomic Landscape in Tlr7-Mediated Demyelination During Aging

Demyelination occurs in aging and associated diseases, including Alzheimers disease. Several of these diseases exhibit sex differences in prevalence and severity. Biological sex primarily stems from sex chromosomes and gonads releasing sex hormones. To dissect mechanisms underlying sex differences in demyelination of aging brains, we constructed a transcriptomic atlas of cell type-specific responses to illustrate how sex chromosomes, gonads, and their interaction shape responses to demyelination. We found that sex-biased oligodendrocyte and microglial responses are driven by interaction of sex chromosomes and gonads prior to myelin loss. Post demyelination, sex chromosomes mainly guide microglial responses, while gonadal composition influences oligodendrocyte signaling. Significantly, ablation of the X-linked gene Toll-like receptor 7 (Tlr7), which exhibited sex-biased expression during demyelination, abolished the sex-biased responses and protected against demyelination. One-sentence summaryCell type-specific processes underlying aged demyelination are sex-biased and mediated by Tlr7.

neuroscience↗

bioRxiv2023

Studies on the International Space Station to assess the effects of microgravity on iPSC-derived neural organoids

Exposure to microgravity in low-Earth orbit (LEO) has been shown to affect human cardiovascular, musculoskeletal, and immune systems. Post-flight brain imaging indicates that reports about astronauts and mouse models suggest that microgravity may cause intracranial fluid shifts and possibly alter white and gray matter of the brain [1]. To focus on the effects of microgravity on the brain, we used induced pluripotent stem cells (iPSCs) to produce three-dimensional (3D) human neural organoids as models of the nervous system. We studied iPSCs derived from four individuals, including people with the neurological diseases primary progressive multiple sclerosis (PPMS) and Parkinsons disease (PD) and non-symptomatic controls. We patterned the organoids toward cortical and dopaminergic fates representing regions of the brain affected by MS and PD, respectively. Microglia were generated from the same cell lines and integrated into a portion of the organoids. The organoids were maintained for 30 days in a novel static culture system on the International Space Station (ISS) and live samples were returned to Earth. The post-flight samples were evaluated using histology, transcriptome and secretome analysis. Microglia-specific genes and secreted proteins were detectable in the microglia-containing organoid cultures. The gene expression analyses of individual organoids cultured in LEO and on Earth suggest that cell proliferation was lower and neural cells were more mature in samples that were cultured in LEO. These experiments lay the groundwork for further studies, including long term studies to investigate the effects of microgravity on the brain. With two more missions using similar cells, we are determining whether this effect of microgravity is consistent in separate experiments. Such studies may ultimately aid in developing countermeasures for the effects of microgravity on the nervous systems of astronauts during space exploration and suggest novel therapeutic interventions for neurological diseases on Earth.

neuroscience↗