Biology subjects

Yang, H.-J.

Publications and source records attributed to Yang, H.-J..

3 recordsLinked to original sources

bioRxiv2026

Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration

Somatic mutations in the de novo DNA methyltransferase DNMT3A are frequent in clonal hematopoiesis, but how they alter the function of differentiated myeloid cells remains unclear. Here, we used isogenic human embryonic stem cell-derived macrophage models to define the consequences of DNMT3A dysfunction during myeloid differentiation. DNMT3A-mutant macrophages selectively upregulated bivalent Polycomb target genes, accompanied by DNA hypomethylation, reduced H3K27me3 and increased promoter accessibility. Despite broad epigenetic changes across bivalent promoters, transcriptional derepression occurred at a subset of loci characterized by lower baseline DNA methylation and higher H3K27me3, identifying pre-existing chromatin state as a determinant of transcriptional response. This Polycomb-associated program was conserved in murine macrophages and enriched for genes involved in cell migration and wound repair. DNMT3A-mutant macrophages exhibited enhanced migration and preferential early recruitment to injured tissue. These findings link clonal hematopoiesis-associated epigenetic alterations to selective transcriptional reprogramming and altered function of differentiated myeloid cells.

cell biology↗

bioRxiv2025

Off-target prediction of SGLT2 inhibitors: an integrative bioinformatics approach to uncover structural mechanisms

Gliflozin is known to inhibit sodium glucose transporter 2 (SGLT2) inhibitors (SGLT2i). They have been approved for the treatments of diabetes mellitus, cardiovascular diseases, and chronic kidney disease in recent years. However, the mechanisms for the multifunction remain unclear. We here propose a hypothesis of other protein targets for gliflozins. Additionally, the multistage of the protein, the specificity of the drugs, along with the structural data shortage have posed a hindrance to disclose gliflozin and its binding environment (BE). Considering the difficulties on the issue, this thesis provides an approach to uncover protein off-targets and to find the underlying pathways. We predicted pyranose was a critical substructure from > 1,500 SGLT2i. Hierarchical clustering on atom-based interaction, combined with propensity, revealed key interaction among 1,572 pyranose BEs. The other criterium presented was the concept of compound spanning space via protein pocket size. Binding sites (BSs) from proteins like SGLT2 were able to provide similar pockets, approximating the occupied space of the ligands. Finally, gliflozin binding pockets prefer (1) aromatic residues for van der Waals force, (2) aspartate or asparagine as hydrogen bond providers, and (3) protein pocket size [greater double equals]442 [A] 2. These criteria were integrated into a scoring function ST and predicted several possible proteins. This research presents a pipeline for target identification of emerging drug agents and proteins with crystallographic difficulties. The study provides an innovative computational methodology on extraction of binding features on transmembrane proteins and further pharmaceutical development.

bioinformatics↗

bioRxiv2017

Asymmetrical localization of components of the Nup107-160 subcomplex within the nuclear pore complex in fission yeast

The nuclear pore complex (NPC) forms a gateway for nucleocytoplasmic transport. The outer ring protein complex of the NPC (the Nup107-160 subcomplex in humans) is a key component for building the NPC. Nup107-160 subcomplexes are believed to be symmetrically localized on the nuclear and cytoplasmic sides of the NPC. However, in S. pombe immunoelectron and fluorescence microscopic analyses revealed that the homologous components of the human Nup107-160 subcomplex had an asymmetrical localization: constituent proteins spNup132 and spNup107 were present only on the nuclear side (designated the spNup132 subcomplex), while spNup131, spNup120, spNup85, spNup96, spNup37, spEly5 and spSeh1 were localized only on the cytoplasmic side (designated the spNup120 subcomplex), suggesting the complex was split into two pieces at the interface between spNup96 and spNup107. This contrasts with the symmetrical localization reported in other organisms. Fusion of spNup96 (cytoplasmic localization) with spNup107 (nuclear localization) caused cytoplasmic relocalization of spNup107. In this strain, half of the spNup132 proteins, which interact with spNup107, changed their localization to the cytoplasmic side of the NPC, leading to defects in mitotic and meiotic progression similar to an spNup132 deletion strain. These observations suggest the asymmetrical localization of the outer ring spNup132 and spNup120 subcomplexes of the NPC is necessary for normal cell cycle progression in fission yeast. Author summaryThe nuclear pore complexes (NPCs) form gateways to transport intracellular molecules between the nucleus and the cytoplasm across the nuclear envelope. The Nup107-160 subcomplex, that forms nuclear and cytoplasmic outer rings, is a key complex responsible for building the NPC by symmetrical localization on the nuclear and cytoplasmic sides of the nuclear pore. This structural characteristic was found in various organisms including humans and budding yeasts, and therefore believed to be common among "all" eukaryotes. However, in this paper, we revealed an asymmetrical localization of the homologous components of the human Nup107-160 subcomplex in fission yeast by immunoelectron and fluorescence microscopic analyses: in this organism, the Nup107-160 subcomplex is split into two pieces, and each of the split pieces is differentially distributed to the nuclear and cytoplasmic side of the NPC: one piece is only in the nuclear side while the other piece is only in the cytoplasmic side. This contrasts with the symmetrical localization reported in other organisms. In addition, we confirmed that the asymmetrical configuration of the outer ring structure is necessary for cell cycle progression in fission yeast. This study provides notions of diverse structures and functions of NPCs evolved in eukaryotes.

cell biology↗