Biology subjects

Im, S.-H.

Publications and source records attributed to Im, S.-H..

3 recordsLinked to original sources

bioRxiv2025

EZH1 Q571R-mediated chromatin compaction and its oncogenic potential in thyroid cancer

Dysregulation of Polycomb Repressive Complex 2 (PRC2) is established to contribute to cancer. Of its catalytic subunits, EZH1 and EZH2, EZH2 mutations in cancer have been extensively identified and studied, but the role of EZH1 in cancer remains largely unexplored. The recurrent presence of the EZH1Q571R mutation in follicular thyroid cancer suggests its involvement in tumor progression. Using EZH1 ChIP-seq, ATAC-seq, and H3K27me3 CUT&Tag, we demonstrated that EZH1Q571R enhances chromatin binding and compaction and stimulates PRC2-EZH1 catalytic activity, leading to increased H3K27me3 levels and repression of tumor suppressor genes. Purified PRC2-EZH1Q571R demonstrated a significant increase in histone methyltransferase activity compared to PRC2-EZH1WT via enhanced nucleosome binding and DNA compaction. Notably, this effect is particularly observed with EZH1Q571R but only to a lesser extent with the corresponding EZH2Q570R mutation, highlighting it as an EZH1-specific mechanism. We additionally demonstrated PRC2-EZH1Q571R to efficiently methylate H3K27 in pre-existing H3K36me2/3 nucleosomes, disrupting chromatin homeostasis. Our findings provide key insights into the molecular pathogenesis of EZH1Q571R-driven follicular thyroid cancer.

molecular biology↗

bioRxiv2024

A Co-essentiality Network of Cancer Driver Genes Better Prioritizes Anticancer Drugs

Diverse molecular networks have been extensively studied to discover therapeutic targets and repurpose approved drugs. However, it is necessary to select a suitable network since the performance of network medicine relies heavily on the completeness and characteristics of the selected network. Although a network using gene essentiality from cancer cells could be an effective platform for identifying anticancer targets, efforts to apply these networks in therapeutic applications have been limited. We constructed a phenotype-level network using the co-essentiality relationship between genes in CRISPR screens across 769 cancer cells to discover therapeutic targets for diverse cancer types. Leveraging cancer driver genes and network propagation on the networks, we found that the co-essentiality network better prioritized anticancer targets and biomarkers and predicted more precise drug responses in cancer cells than other molecular networks. The co-essentiality network outperformed conventional molecular networks in drug repurposing, which were validated in silico by clinical trial records. Notably, the co-essentiality network provided 37 repurposed drugs that the other networks have yet to cover, and we showcased three approved drugs repurposed for lung adenocarcinoma (Pioglitazone hydrochloride, Atovaquone, and Eflornithine). Our study provides a novel network for precision oncology to improve the identification of therapeutic targets in specific cancers.

bioinformatics↗

bioRxiv2024

B lymphocytes acquire myeloid and autoimmune phenotypes via the downregulation of lymphocyte-specific protein-1

Actin-binding proteins (ABPs) have been established as important mediators of immune homeostasis, but their effects on lymphocytes are poorly understood. Here, we demonstrated that LSP1, an ABP, is a master regulator for innate immune responses in B lymphocytes. Lsp1 deficiency in B cells upregulated the expression of myeloid genes, including CD11b, CD11c, and myeloperoxidase, and bestowed myeloid morphology. Strikingly, Lsp1-deficient B cells exhibited dual functions, namely, strong phagocytic activity and high antibody (Ab) production, like chimera. The PKC{beta}-CEBP{beta} pathway was found to be required for such functional chimerism. Moreover, Lsp1 deficiency induced the myeloid B cell phenotype and autoantibody production in B cells and consequently accelerated the progression of experimental lupus in mice. These changes were abrogated by retinoic acid, which upregulated LSP1 expression. In lupus patients, LSP1 expression in B cells was downregulated and inversely correlated with myeloperoxidase (MPO) expression. Overall, this study reveals a new role of the ABP LSP1 in B lymphocytes and emphasizes its critical involvement in promoting autoimmune responses, particularly by generating functionally chimeric B cells.

immunology↗