Biology subjects

Mun, M.

Publications and source records attributed to Mun, M..

3 recordsLinked to original sources

bioRxiv2025

GATA2 Mediates Macrophage Proliferation During Atherosclerosis

Atherosclerosis is fueled by the buildup of lipid-laden macrophages within the vascular intima. These macrophages are derived from monocytes that are recruited from the circulation into the developing lesion, where they proliferate and differentiate into macrophages, with proliferation producing most of the macrophages in the resulting lesions. However, the signals and transcriptional events driving the proliferation of atherosclerotic plaque macrophages remain poorly understood. Analysis of human plaque spanning a range of disease severity identified a subpopulation of macrophages that expressed the hematopoietic transcription factor GATA2. These GATA2-expressing macrophages had a transcriptional profile that was intermediary between monocytes and mature macrophages, and selectively upregulated genes associated with proliferation and apoptosis. The expression of GATA2 was concomitant with plaque macrophage proliferation at all stages of disease, with over 90% of proliferating macrophages expressing GATA2. GATA2 was upregulated in macrophages following exposure to oxLDL, with GATA2 expression being necessary and sufficient for the proliferation of these macrophages. In these cells, GATA2 mediates proliferation by upregulating expression of the proto-oncogene MYB, while simultaneously decreasing sensitivity to apoptosis induced by the unfolded protein response. Together, these data identify GATA2 as a transcription factor upregulated by atherogenic stimuli that functions as the primary mediator of macrophage proliferation in atherosclerotic plaque.

immunology↗

bioRxiv2025

Database Permeating through Time, Space, and Medicine: A sequence, structure, and clinical compilation and comparison of transmembrane amino acids in VGL ion channels

Ion channels of the VGL superfamily are extremely diverse in their physiological roles - critical in all excitable cells. Mutations in these channels can cause clinical deficits and symptomologies. With recent advances in sequencing and structural data in the past 30 years, there is a plethora of bioinformatic information that experimentalists can utilize to draw hypotheses about structure and function. However, there is no cohesive database that has compiled this data and presents it in an easily accessible and avoids the confounds of close evolutionary lineages. Here, we seek to fill this gap in resources by compiling and comparing groups of sequences and structures across many channels of the VGL superfamily. Additionally, we corroborate the well-conserved amino acid positions with previous experimental work as well as put forth some understudied but well-conserved amino acid positions that might be fundamental to the certain generalizable mechanisms present in the VGL superfamily channels. To further lend evidence to understudied positions being critical to certain generalizable mechanisms, we also compiled clinical mutation data at these positions across many channels to show the likely functional relevance of these positions. Finally, we will make all of the alignments and resources we generated publicly available at https://github.com/Frank-Yeh-95/VGLDatabaseCompilation for ease of hypothesis generation.

biophysics↗

bioRxiv2024

Identification of Druggable Binding Sites and Small Molecules as Modulators of TMC1

Our ability to hear and maintain balance relies on the proper functioning of inner ear sensory hair cells, which translate mechanical stimuli into electrical signals via mechano-electrical transducer (MET) channels, composed of TMC1/2 proteins. However, the therapeutic use of ototoxic drugs, such as aminoglycosides and cisplatin, which can enter hair cells through MET channels, often leads to profound auditory and vestibular dysfunction. Despite extensive research on otoprotective compounds targeting MET channels, our understanding of how small-molecule modulators interact with these channels remains limited, hampering the discovery of novel drugs. Here, we propose a structure-based screening approach, integrating 3D-pharmacophore modeling, molecular dynamics simulations of the TMC1+CIB2+TMIE complex, and experimental validation. Our pipeline successfully identified several novel compounds and FDA-approved drugs that reduced dye uptake in cultured cochlear explants, indicating MET-modulation activity. Simulations, molecular docking and free-energy estimations allowed us to identify three potential drug-binding sites within the channel pore, phospholipids, key amino acids involved in modulator interactions, and TMIE as a flexible component of the MET complex. We also identified shared ligand-binding features between TMC and structurally related TMEM16 proteins, providing novel insights into their distinct inhibition. Our pipeline offers a broad application for discovering modulators for mechanosensitive ion channels.

neuroscience↗