Biology subjects

Harris, C. J.

Publications and source records attributed to Harris, C. J..

3 recordsLinked to original sources

bioRxiv2024

Asiatic acid improves mitochondrial function, activates antioxidant response in the mouse brain and improves cognitive function in beta-amyloid overexpressing mice.

Extracts of the plant Centella asiatica can enhance mitochondrial function, promote antioxidant activity and improve cognitive deficits. Asiatic acid (AA) is one of the constituent triterpene compounds present in the plant. In this study we explore the effects of increasing concentrations of AA on brain mitochondrial function, antioxidant response and cognition in healthy mice and a single concentration of AA in the beta-amyloid overexpressing 5xFAD mouse line. Associative memory and overall activity were assessed. Hippocampal mitochondrial bioenergetics and the expression of mitochondrial and antioxidant response genes was determined. In the 5xFAD line, total beta-amyloid plaque burden after AA treatment was also evaluated. In healthy mice, we report dose responsive effects of increasing concentrations of AA on enhanced associative memory and a dose dependent increase in basal and maximal mitochondrial respiration, mitochondrial gene expression and antioxidant gene expression. Results from the highest AA dose (1% AA) were similar to what was observed with CAW. The high AA dose was then evaluated in the context of A{beta} accumulation in 5xFAD mice. Improvements in mitochondrial and antioxidant response genes were favored in females over males without significant alleviation of A{beta} plaque burden.

neuroscience↗

bioRxiv2023

H1 restricts euchromatin-associated methylation pathways from heterochromatic encroachment

Silencing pathways prevent transposable element (TE) proliferation and help to maintain genome integrity through cell division. Silenced genomic regions can be classified as either euchromatic or heterochromatic, and are targeted by genetically separable epigenetic pathways. In plants, the RNA-directed DNA methylation (RdDM) pathway targets mostly euchromatic regions, while CMT DNA methyltransferases are mainly associated with heterochromatin. However, many epigenetic features - including DNA methylation patterning - are largely indistinguishable between these regions, so how the functional separation is maintained is unclear. The linker histone H1 is preferentially localized to heterochromatin and has been proposed to restrict RdDM from encroachment. To test this hypothesis, we followed RdDM genomic localization in an h1 mutant by performing ChIP-seq on the largest subunit, NRPE1, of the central RdDM polymerase, Pol V. Loss of H1 resulted in NRPE1 enrichment predominantly in heterochromatic TEs. Increased NRPE1 binding was associated with increased chromatin accessibility in h1, suggesting that H1 restricts NRPE1 occupancy by compacting chromatin. However, RdDM occupancy did not impact H1 localization, demonstrating that H1 hierarchically restricts RdDM positioning. H1 mutants experience major symmetric (CG and CHG) DNA methylation gains, and by generating an h1/nrpe1 double mutant, we demonstrate these gains are largely independent of RdDM. However, loss of NRPE1 occupancy from a subset of euchromatic regions in h1 corresponded to loss of methylation in all sequence contexts, while at ectopically bound heterochromatic loci, NRPE1 deposition correlated with increased methylation specifically in the CHH context. Additionally, we found that H1 similarly restricts the occupancy of the methylation reader, SUVH1, and polycomb-mediated H3K27me3. Together, the results support a model whereby H1 helps maintain the exclusivity of heterochromatin by preventing encroachment from other competing pathways.

plant biology↗

bioRxiv2022

MORC proteins regulate transcription factor binding by mediating chromatin compaction in active chromatin regions

BackgroundThe Microrchidia (MORC) proteins are a family of evolutionarily conserved GHKL-type ATPases involved in chromatin compaction and gene silencing. Arabidopsis MORC proteins act in the RNA-directed DNA methylation (RdDM) pathway, where they act as molecular tethers to ensure the efficient establishment of RdDM and de novo gene silencing. However, MORC proteins also have RdDM-independent functions; although, their underlying mechanisms are unknown. ResultsIn this study, we examined regions of MORC binding where RdDM does not occur in order to shed light on the RdDM-independent functions of MORC proteins. We found that MORC proteins compact chromatin and reduce DNA accessibility to transcription factors (TFs), thereby repressing gene expression. We also found that MORC-mediated repression of gene expression was particularly important under conditions of stress. We showed that MORC proteins regulate TFs through either direct or indirect interactions, and these TFs can in some cases regulate their own transcription, resulting in feedforward loops. ConclusionsOur findings provide insights into the molecular mechanisms of MORC-mediated chromatin compaction and transcription regulation.

plant biology↗