ABSTRACT
BACKGROUND: Linker histones establish and maintain higher-order chromatin structure. Eleven linker histone subtypes have been reported in mammals. HILS1 is a spermatid-specific linker histone, and its expression overlaps with the histone-protamine exchange process during mammalian spermiogenesis. However, the role of HILS1 in spermatid chromatin remodeling is largely unknown. RESULTS: In this study, we demonstrate using circular dichroism spectroscopy that HILS1 is a poor condenser of DNA and chromatin compared to somatic linker histone H1d. Genome-wide occupancy study in elongating/condensing spermatids revealed the preferential binding of HILS1 to the LINE-1 (L1) elements within the intergenic and intronic regions of rat spermatid genome. We observed specific enrichment of the histone PTMs like H3K9me3, H4K20me3 and H4 acetylation marks (H4K5ac and H4K12ac) in the HILS1-bound chromatin complex, whereas H3K4me3 and H3K27me3 marks were absent. CONCLUSIONS: HILS1 possesses significantly lower α-helicity compared to other linker histones such as H1t and H1d. Interestingly, in contrast to the somatic histone variant H1d, HILS1 is a poor condenser of chromatin which demonstrate the idea that this particular linker histone variant may have distinct role in histone to protamine replacement. Based on HILS1 ChIP-seq analysis of elongating/condensing spermatids, we speculate that HILS1 may provide a platform for the structural transitions and forms the higher-order chromatin structures encompassing LINE-1 elements during spermiogenesis.
Subject(s)
Chromatin/genetics , DNA-Binding Proteins/metabolism , DNA/genetics , Spermatids/metabolism , Animals , DNA-Binding Proteins/chemistry , Histones/metabolism , Long Interspersed Nucleotide Elements , Male , Protein Processing, Post-Translational , Protein Structure, Secondary , Rats , Spermatids/chemistryABSTRACT
Idiopathic Parkinson's disease and manganese-induced atypical parkinsonism are characterized by movement disorder and nigrostriatal pathology. Although clinical features, brain region involved and responsiveness to levodopa distinguish both, differences at the neuronal level are largely unknown. We studied the morphological, neurophysiological and molecular differences in dopaminergic neurons exposed to the Parkinson's disease toxin 1-methyl-4-phenylpyridinium ion (MPP+ ) and manganese (Mn), followed by validation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and Mn mouse models. Morphological analysis highlighted loss of neuronal processes in the MPP+ and not the Mn model. Cellular network dynamics of dopaminergic neurons characterized by spike frequency and inter-spike intervals indicated major neuronal population (~ 93%) with slow discharge rates (0-5 Hz). While MPP+ exposure suppressed the firing of these neurons, Mn neither suppressed nor elevated the neuronal activity. High-throughput transcriptomic analysis revealed up-regulation of 694 and 603 genes and down-regulation of 428 and 255 genes in the MPP+ and Mn models respectively. Many differentially expressed genes were unique to either models and contributed to neuroinflammation, metabolic/mitochondrial function, apoptosis and nuclear function, synaptic plasticity, neurotransmission and cytoskeleton. Analysis of the Janus kinase-signal transducer and activator of transcription pathway with implications for neuritogenesis and neuronal proliferation revealed contrasting profile in both models. Genome-wide DNA methylomics revealed differences between both models and substantiated the epigenetic basis of the difference in the Janus kinase-signal transducer and activator of transcription pathway. We conclude that idiopathic Parkinson's disease and atypical parkinsonism have divergent neurotoxicological manifestation at the dopaminergic neuronal level with implications for pathobiology and evolution of novel therapeutics. Cover Image for this issue: doi. 10.1111/jnc.13821.
Subject(s)
1-Methyl-4-phenylpyridinium/toxicity , Dopaminergic Neurons/drug effects , Gene Expression Regulation/drug effects , Manganese/toxicity , Neurotoxins/toxicity , Action Potentials/drug effects , Animals , Apoptosis/drug effects , Behavior, Animal/drug effects , Cell Line, Transformed , Cell Survival/drug effects , DNA Methylation/drug effects , Dopaminergic Neurons/cytology , Dopaminergic Neurons/ultrastructure , L-Lactate Dehydrogenase/metabolism , Male , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Inbred C57BL , Neural Networks, Computer , Rats , Signal Transduction/drug effects , Transcriptome/drug effects , Transcriptome/physiology , Tyrosine 3-Monooxygenase/metabolismABSTRACT
We have reported results from the formative stage of a community health worker intervention designed to improve diabetes management among Bangladeshi patients in New York City. Trained community health workers conducted focus groups (n = 47) and surveys (n = 169) with Bangladeshi individuals recruited from community locations. Results indicated that participants faced numerous barriers to care, had high rates of limited English proficiency, and had low levels of knowledge about diabetes. Most participants expressed interest in participating in a community health worker intervention.
