Biology subjects

Hwang, E.

Publications and source records attributed to Hwang, E..

9 recordsLinked to original sources

bioRxiv2026

Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

genetics↗

bioRxiv2025

Acute Myeloid Leukemia Relapse after Bromodomain Inhibitor Treatment or Chemotherapy is Characterized by Myc-Ras Transcriptional Remodeling

Adult and pediatric acute myeloid leukemias (AMLs) harbor distinct mutational profiles, including a higher incidence of RAS and other signaling mutations in young patients. Here we show that the BET inhibitor PLX51107 potently suppresses the growth of NRAS-mutant AML cell lines, and that these activities are enhanced by co-treatment with the MEK inhibitor PD0325901. Controlled preclinical trials in primary mouse Nras-mutant AMLs revealed single agent efficacy of PLX51107 that was enhanced by PD0325901. Leukemias that relapsed during treatment developed intrinsic drug resistance characterized by transition to a more primitive state, up-regulation of Myc target genes, and down-regulation of Ras-associated transcriptional programs. AMLs that relapsed after frontline chemotherapy showed similar transcriptional remodeling. These studies demonstrate transcriptional plasticity in primary AMLs that relapse following in vivo treatment with either targeted agents or chemotherapy, and support evaluating BET inhibition in leukemias with monocytic differentiation and RAS mutations.

cancer biology↗

bioRxiv2024

Cav3.1 is a leucine sensor in POMC neurons mediating appetite suppression and weight loss

Hypothalamic leucine sensing promotes satiety and weight loss but an understanding of how leucine regulates neuronal activity is lacking. Here we show that Cacna1g, encoding the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of POMC neurons as well as the anorectic response to leucine in vivo. In addition, genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, we show that leucine binds to the voltage-sensing segment of Cav3.1, thereby reducing its threshold for voltage-dependent activation. Last, pharmacological activation of hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates the weight loss response to GLP-1 receptor agonism. These results reveal that Cav3.1 is a neuronal leucine sensor and a relevant weight loss target.

neuroscience↗

bioRxiv2024

Metapipeline-DNA: A Comprehensive Germline & Somatic Genomics Nextflow Pipeline

SummaryThe price, quality and throughout of DNA sequencing continue to improve. Algorithmic innovations have allowed inference of a growing range of features from DNA sequencing data, quantifying nuclear, mitochondrial and evolutionary aspects of both germline and somatic genomes. To automate analyses of the full range of genomic characteristics, we created an extensible Nextflow meta-pipeline called metapipeline-DNA. Metapipeline-DNA analyzes targeted and whole-genome sequencing data from raw reads through pre-processing, feature detection by multiple algorithms, quality-control and data- visualization. Each step can be run independently and is supported robust software engineering including automated failure-recovery, robust testing and consistent verifications of inputs, outputs and parameters. Metapipeline-DNA is cloud-compatible and highly configurable, with options to subset and optimize each analysis. Metapipeline-DNA facilitates high-scale, comprehensive analysis of DNA sequencing data. AvailabilityMetapipeline-DNA is an open-source Nextflow pipeline under the GPLv2 license and is available at https://github.com/uclahs-cds/metapipeline-DNA.

bioinformatics↗

bioRxiv2023

The non-mitotic role of HMMR in regulating the localization of TPX2 and the dynamics of microtubules in neurons

A functional nervous system is built upon the proper morphogenesis of neurons to establish the intricate connection between them. The microtubule cytoskeleton is known to play various essential roles in this morphogenetic process. While many microtubule-associated proteins (MAPs) have been demonstrated to participate in neuronal morphogenesis, the function of many more remains to be determined. This study focuses on a MAP called HMMR, which was originally identified as a hyaluronan binding protein and later found to possess microtubule and centrosome binding capacity. HMMR exhibits high abundance on neuronal microtubules and altering the level of HMMR significantly affects the morphology of neurons. Instead of confining to the centrosome(s) like cells in mitosis, HMMR localizes to microtubules along axons and dendrites. Furthermore, transiently expressing HMMR enhances the stability of neuronal microtubules and increases the formation frequency of growing microtubules along the neurites. HMMR regulates the microtubule localization of a non-centrosomal microtubule nucleator TPX2 along the neurite, offering an explanation for how HMMR contributes to the promotion of growing microtubules. This study sheds light on how progenitor cells utilize proteins involved in mitosis for non-mitotic functions.

cell biology↗

bioRxiv2022

Rewiring Dynamics of Functional Connectome in Motor Cortex during Motor Skill Learning

The brains connectome continually rewires throughout the life of an organism. In this study, we sought to elucidate the operational principles of such rewiring by analyzing the functional connectomes in mouse primary motor cortex (M1) during a 14-session (day) lever-press task learning in response to an auditory cue. Specifically, we employed Calcium imaging recordings of L2/3 and L5 of M1 in awake mice to reconstruct and analyze functional connectomes across learning sessions. Our results show that functional connectomes in L2/3 and L5 follow a similar learning-induced rewiring trajectory. More specifically, the connectomes rewire in a biphasic manner, where functional connectivity increases over the first few learning sessions, and then, it is gradually pruned to return to a homeostatic level of network density. We demonstrated that the increase of network connectivity in L2/3 connectomes, but not in L5, generates neuronal co-firing activity that correlates with higher motor performance (shorter cue-to-reward time), while motor performance remains relatively stable throughout the pruning phase. The results show a biphasic rewiring principle that involves the maximization of reward / performance and maintenance of network density. Finally, we demonstrated that the connectome rewiring in L2/3 is clustered around a core set of movement-associated neurons that form a highly interconnected hub in the connectomes, and that the activity of these core neurons stably encodes movement throughout learning. Significance StatementConnectomes in the motor cortex rewire during motor skill learning, but the operational principle behind this rewiring is yet to be determined. Here, we characterized the rewiring dynamics of functional connectomes in L2/3 and L5 of M1 in mice engaging in a lever-press learning, using two-photon fluorescence microscopy data. We identified a universal biphasic rewiring trajectory across animals and layers in the motor cortex that reflects two objectives: an exploratory phase that increases functional connectivity and optimizes motor performance, and a pruning phase that brings connectivity back to a homeostatic level while maintaining motor performance. We found further that connectome rewiring during motor skill learning concentrates around a core set of highly interconnected neurons in L2/3 that reliably encode movements.

neuroscience↗

bioRxiv2020

FARCI: Fast and Robust Connectome Inference

The inference of neuronal connectome from large-scale neuronal activity recordings, such as two-photon Calcium imaging, represents an active area of research in computational neuroscience. In this work, we developed FARCI (Fast and Robust Connectome Inference), a MATLAB package for neuronal connectome inference from high-dimensional two-photon Calcium fluorescence data. We employed partial correlations as a measure of the functional association strength between pairs of neurons to reconstruct a neuronal connectome. We demonstrated using gold standard datasets from the Neural Connectomics Challenge (NCC) that FARCI provides an accurate connectome and its performance is robust to network sizes, missing neurons, and noise levels. Moreover, FARCI is computationally efficient and highly scalable to large networks. In comparison to the best performing algorithm in the NCC, FARCI produces more accurate networks over different network sizes and subsampling, while providing over two orders of magnitude faster computational speed.

neuroscience↗

bioRxiv2020

miR6236, a microRNA suppressed by the anisotropic surface topography, regulates neuronal development and regeneration.

It has been well studied that the surface topography affects the growth and development of neurons. However, the precise mechanism that the surface topography leads to cellular changes remains unknown. In this study, we created an anisotropic surface using nanodiamonds and discovered this surface topography accelerates the development of primary neurons from both the central and peripheral nervous systems. Using RNA sequencing technology, a previously uncharacterized microRNA (miR6236) was found to exhibit significant and the most substantial decrease when neurons are cultured on this nanodiamond surface. Gain- and loss-of-function assays confirm that miR6236 is the predominant molecule responsible for converting the surface topography into biological responses. We further demonstrate that the depletion of miR6236 can enhance neuroregeneration on inhibitory substrate, uncovering its therapeutic potential for promoting central nervous system regeneration.

neuroscience↗

bioRxiv2019

Ran GTPase regulates non-centrosomal microtubule nucleation and is transported by actin waves towards the neurite tip.

Microtubule (MT) is the most abundant cytoskeleton in neurons and controls multiple facets of their development. While the organizing center of MTs in mitotic cells is typically located at the centrosome, MT nucleation in post-mitotic neurons switches to non-centrosomal sites. A handful of proteins and organelle have been shown to promote non-centrosomal MT formation in neurons, yet the regulation mechanism remains unknown. Here we demonstrate that the small GTPase Ran is a key regulator of non-centrosomal MT nucleation in neurons. The GTP-bound Ran (RanGTP) localizes to the neurite tips and around the soma. Using the RanGTP- and RanGDP-mimic mutants, we show that RanGTP promotes MT nucleation at the tip of the neurite. To demonstrate that RanGTP can promote MT nucleation in regions other than the neurite tip, an optogenetic tool called RanTRAP was constructed to enable light-induced local production of RanGTP in the neuronal cytoplasm. An increase of non-centrosomal MT nucleation can be observed by elevating the RanGTP level along the neurite using RanTRAP, establishing a new role for Ran in regulating neuronal MTs. Additionally, the mechanism of RanGTP enrichment at the neurite tip was examined. We discovered that actin waves drive the anterograde transport of RanGTP towards the neurite tip. Pharmacological disruption of actin waves abolishes the enrichment of RanGTP and reduces the non-centrosomal MT nucleation at the neurite tip. These observations provide a novel regulation mechanism of MTs and an indirect connection between the actin and MT cytoskeletons in neurons.

cell biology↗