Biology subjects

Langberg, S.

Publications and source records attributed to Langberg, S..

2 recordsLinked to original sources

bioRxiv2024

APOE regulates the transport of GM1

Apolipoprotein E (APOE) is responsible for lipid transport, including cholesterol transport and clearance. While the {varepsilon}4 allele of APOE (APOE4) is associated with a significant genetic risk factor for late-onset Alzheimers disease (AD), no mechanistic understanding of its contribution to AD etiology has been established yet. In addition to cholesterol, monosialotetrahexosylganglioside (GM1) is a crucial lipid component in cell membranes and has been implicated in promoting the aggregation of amyloid beta protein (A{beta}), a key protein associated with AD. Here, we ask whether there are direct interactions between APOE and GM1 that further impact AD pathology. We find that both APOE3 and APOE4 exhibit superior binding affinity to GM1 compared to cholesterol and have an enhanced cellular uptake to GM1 lipid structures than cholesterol lipid structures. APOE regulates the transport process of GM1 depending on the cell type, which is influenced by the expression of APOE receptors in different cell lines and alters GM1 contents in cell membranes. We also find that the presence of GM1 alters the secondary structure of APOE3 and APOE4 and enhances the binding affinity between APOE and its receptor low-density lipoprotein receptor (LDLR), consequently promoting the cellular uptake of lipid structures in the presence of APOE. To understand the enhanced cellular uptake observed in lipid structures containing 20% GM1, we determined the distribution of GM1 on the membrane and found that GM1 clustering in lipid rafts, thereby supporting the physiological interaction between APOE and GM1. Overall, we find that APOE plays a regulatory role in GM1 transport, and the presence of GM1 on the lipid structures influences this transport process. Our studies introduce a plausible direct link between APOE and AD etiology, wherein APOE regulates GM1, which, in turn, promotes A{beta} oligomerization and aggregation.

neuroscience↗

bioRxiv2021

Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer

Breast cancer is a highly heterogeneous disease driven by multiple factors including genetic and epigenetic alterations. DNA methylation patterns have been shown to be altered on a genome-wide scale and previous studies have highlighted the critical role of aberrant DNA methylation on gene expression and breast cancer pathogenesis. Here, we perform genome-wide expression-methylation Quantitative Trait Loci (emQTL), a method for integration of CpG methylation and gene expression to identify disease-driving genes under epigenetic control. By grouping these emQTLs by biclustering we identify associations representing important biological processes associated with breast cancer pathogenesis such as proliferation and tumor infiltrating fibroblasts. We report hypomethylation at enhancers carrying transcription factor binding sites of key proliferation-driving transcription factors such as CEBP-{beta}, FOSL1, and FOSL2, with concomitant high expression of cell cycle- and proliferation-related genes in aggressive breast tumors. The identified CpGs and genes were found to be connected through chromatin loops, together indicating that proliferation in aggressive breast tumors is under epigenetic regulation by DNA methylation. Interestingly, there was a significant correlation between proliferation-related DNA methylation and gene expression also within subtypes of breast cancer, thereby showing that varying proliferation may be explained by epigenetic profiles across breast cancer subtypes. Indeed, the identified proliferation gene signature was prognostic both in the Luminal A and Luminal B subtypes. Taken together, we show that proliferation in breast cancer is linked to hypomethylation at specific enhancers and transcription factor binding mediated through chromatin loops.

cancer biology↗