Biology subjects

Brown, A. K.

Publications and source records attributed to Brown, A. K..

7 recordsLinked to original sources

bioRxiv2026

Glial cells gate small RNA transport from germline to brain during transgenerational epigenetic inheritance of behavior

How circulating RNAs reach their target tissue is not well understood. In C. elegans, small RNA signals that convey exposure to pathogenic Pseudomonas travel from the intestine to germline to neurons, allowing both learned pathogen avoidance and the transgenerational inheritance of this information for four generations, but how this Cer1 retrotransposon-bound RNA signal reaches the nervous system was previously unknown. We found that the RNA transporter SID-1, long thought to act in the intestine or germline, instead functions in a single cell type, the amphid sheath glia, where it is necessary and sufficient for learned avoidance. SID-1 mediates uptake of germline-derived RNA, followed by transcytosis to a neighboring sensory neuron, where the P11 target gene maco-1 is silenced. This glial "filter", which uses highly conserved molecular components to transcytose RNAs to neurons, reveals a general mechanism for gating small RNA access to the nervous system, paralleling the mammalian blood-brain barrier.

genetics↗

bioRxiv2025

Neuronal SET1/COMPASS-mediated epigenetic regulation of de novo transcription drives accelerated forgetting with age

Forgetting is a critical component of memory, but its molecular regulation - particularly with age - is not well understood. Epigenetic modifications are a candidate for this regulation and may further drive age-related behavioral decline, as they are dramatically altered in the aging brain. We found that multiple components of the SET1/COMPASS complex, a conserved histone methyltransferase complex associated with active gene transcription, are upregulated with age in the C. elegans nervous system. Neuronal knockdown of the SET1/COMPASS components improves memory in young adult animals and slows memory decline in old animals. By pharmacological and genetic inhibition, optogenetics, and neuronal mRNA and chromatin profiling, we demonstrate that SET1/COMPASS-mediated active transcription promotes forgetting. SET1/COMPASS regulates the de novo activity-dependent transcription and release of a neuropeptidergic signal from the AWC olfactory sensory neuron, which erases the associative memory trace in downstream motor neurons, resulting in forgetting. We further found that increased SET1/COMPASS-dependent chromatin accessibility at these gene loci with age primes these loci for transcription, resulting in accelerated forgetting. Our results reveal the role of active gene transcription in the regulation of forgetting and altered SET1/COMPASS-mediated gene transcription as a mechanism of cognitive decline, implicating increased expression of COMPASS components as a driver of increased forgetting in the aging brain. This mechanism may offer a new target for slowing loss of cognitive function with age.

neuroscience↗

bioRxiv2024

CryoEM structure of the di-domain core of Mycobacterium tuberculosis polyketide synthase 13, essential for mycobacterial mycolic acid synthesis.

Mycobacteria are known for their complex cell wall, which comprises layers of peptidoglycan, polysaccharides and unusual fatty acids known as mycolic acids that form their unique outer membrane. Polyketide synthase 13 (Pks13) of Mycobacterium tuberculosis, the bacterial organism causing tuberculosis (TB), catalyses the last step of mycolic acid synthesis prior to export to and assembly in the cell wall. Due to its essentiality, Pks13 is a target for several novel anti-tubercular inhibitors, but its 3D structure and catalytic reaction mechanism remain to be fully elucidated. Here, we report the molecular structure of the catalytic core domains of M. tuberculosis Pks13 (Mt-Pks13), determined by transmission cryo-electron microscopy (cryoEM) to a resolution of 3.4 [A]. We observe a homodimeric assembly comprising the ketoacyl synthase (KS) domain at the centre, mediating dimerization, and the acyltransferase (AT) domains protruding in opposite directions from the central KS domain dimer. In addition to the KS-AT di-domains, the cryoEM map includes features not covered by the di-domain structural model that we predict to contain a dimeric domain with similarity to dehydratases, yet likely lacking catalytic function. Analytical ultracentrifugation data indicate a pH-dependent equilibrium between monomeric and dimeric assembly states, while comparison with the previously determined structures of M. smegmatis Pks13 indicates architectural flexibility. Combining the experimentally determined structure with modelling in AlphaFold2 suggests a structural scaffold with a relatively stable dimeric core, that combines with considerable conformational flexibility to facilitate the successive steps of the Claisen-type condensation reaction catalysed by Pks13.

microbiology↗

bioRxiv2023

CD36-Pyruvate Kinase M2 Signaling Promotes Macrophage Phagocytosis Through Mitochondrial Reactive Oxygen Species

Macrophage efferocytosis, the process by which phagocytes engulf and remove apoptotic cells (ACs), plays a critical role in maintaining tissue homeostasis. Efficient efferocytosis prevents secondary necrosis, mitigates chronic inflammation, and impedes atherosclerosis progression. However, the regulatory mechanisms of efferocytosis under atherogenic conditions remain poorly understood. We previously demonstrated that oxidized LDL (oxLDL), an atherogenic lipoprotein, induces mitochondrial reactive oxygen species (mtROS) in macrophages via CD36. In this study, we demonstrate that macrophage mtROS facilitate continual efferocytosis through a positive feedback mechanism. However, oxLDL disrupts continual efferocytosis by dysregulating the internalization of ACs. This disruption is mediated by an overproduction of mtROS. Mechanistically, oxLDL/CD36 signaling promotes the translocation of cytosolic PKM2 to mitochondria, facilitated by the chaperone GRP75. Mitochondrial PKM2 then binds to Complex III of the electron transport chain, inducing mtROS production. This study elucidates a novel regulatory mechanism of efferocytosis in atherosclerosis, providing potential therapeutic targets for intervention. SUMMARYMacrophages clear apoptotic cells through a process called efferocytosis, which involves mitochondrial ROS. However, the atherogenic oxidized LDL overstimulates mitochondrial ROS via the CD36-PKM2 pathway, disrupting continual efferocytosis. This finding elucidates a novel molecular mechanism that explains defects in efferocytosis, driving atherosclerosis progression.

immunology↗

bioRxiv2021

Integrative multi-omics analysis reveals conserved hierarchical mechanisms of FOXO3 pioneer-factor activity

FOXO transcription factors are critical for cellular homeostasis and have been implicated in longevity in several species. Yet how these factors directly affect aging, particularly in humans, is not well understood. Here, we take an integrated multi-omics approach to identify the chromatin-level mechanisms by which FOXO3 coordinates transcriptional programs. We find that FOXO3 functions as a pioneer factor in human cells, directly altering chromatin accessibility to regulate gene expression. Unexpectedly, FOXO3s pioneer activity at many sites is achieved through a two-step process, in which chromatin accessibility is initially reduced, then transitions to an open conformation. The direct FOXO3 network comprises chromatin remodelers, including the SWI/SNF remodeling complex, which we find is functionally required for FOXO3 activity. We also identify a novel secondary network of activator protein-1 (AP-1) transcription factors deployed by FOXO3, which orchestrate a neuronal-specific subnetwork. Together, this hierarchical FOXO3 pioneer network regulates key cellular processes including metabolism, proteostasis, epigenetics and proliferation, which must be tightly controlled under changing conditions that accompany aging.

cell biology↗

bioRxiv2020

Infanticide by females is a leading source of juvenile mortality in a large social carnivore

Social animals benefit from their groupmates, so why do they sometimes kill each others offspring? Using 30 years of data from multiple groups of wild spotted hyenas, we address three critical aims for understanding infanticide in any species: (1) quantify the contribution of infanticide to overall mortality (2) describe the circumstances under which infanticide occurs and (3) evaluate hypotheses about the evolution of infanticide. We find that, although observed only rarely, infanticide is in fact a leading source of juvenile mortality. Infanticide accounted for 24% of juvenile mortality, and 1 in 10 hyenas born in our population perished due to infanticide. In all observed cases of infanticide, killers were adult females, but victims could be of both sexes. Of four hypotheses regarding the evolution of infanticide, we found the most support for the hypothesis that infanticide in spotted hyenas reflects competition over social status among matrilines.

animal behavior and cognition↗

bioRxiv2020

Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation

Adult neural stem cells are largely quiescent, and require transcriptional reprogramming to reenter the cell cycle and undergo neurogenesis. However, the precise mechanisms that underlie the rapid transcriptional overhaul during NSC activation remain undefined. Here, we identify the genome-wide chromatin accessibility differences between primary neural stem and progenitor cells in quiescent and activated states. We show that these distinct cellular states exhibit both shared and unique chromatin profiles, which are both associated with gene regulation. Interestingly, we find that accessible chromatin states specific to quiescent or activated cells are active enhancers bound by pro-neurogenic and quiescence factors, ASCL1 and NFI. In contrast, shared sites are gene promoters harboring constitutively accessible chromatin enriched for particular core promoter elements that are functionally associated with translation and metabolic functions. Together, our findings reveal how accessible chromatin states regulate a transcriptional overhaul and drive the switch between quiescence and proliferation in NSC activation.

molecular biology↗