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1.
Mol Neurobiol ; 60(5): 2937-2953, 2023 May.
Article in English | MEDLINE | ID: mdl-36750527

ABSTRACT

Spinal cord injury is a severely debilitating condition affecting a significant population in the USA. Spinal cord injury patients often have increased risk of developing persistent neuropathic pain and other neurodegenerative conditions beyond the primary lesion center later in their life. The molecular mechanism conferring to the "latent" damages at distal tissues, however, remains elusive. Here, we studied molecular changes conferring abnormal functionality at distal spinal cord (T12) beyond the lesion center (T10) by combining next-generation sequencing (RNA- and bisulfite sequencing), super-resolution microscopy, and immunofluorescence staining at 7 days post injury. We observed significant transcriptomic changes primarily enriched in neuroinflammation and synaptogenesis associated pathways. Transcription factors (TFs) that regulate neurogenesis and neuron plasticity, including Egr1, Klf4, and Myc, are significantly upregulated. Along with global changes in chromatin arrangements and DNA methylation, including 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), bisulfite sequencing further reveals the involvement of DNA methylation changes in regulating cytokine, growth factor, and ion channel expression. Collectively, our results pave the way towards understanding transcriptomic and epigenomic mechanism in conferring long-term disease risks at distal tissues away from the primary lesion center and shed light on potential molecular targets that govern the regulatory mechanism at distal spinal cord tissues.


Subject(s)
Contusions , Spinal Cord Injuries , Rats , Animals , Epigenesis, Genetic , Transcriptome/genetics , Epigenomics/methods , Spinal Cord Injuries/genetics , Spinal Cord Injuries/pathology , DNA Methylation/genetics , Spinal Cord/pathology
2.
Elife ; 92020 05 18.
Article in English | MEDLINE | ID: mdl-32420875

ABSTRACT

Modulating cytoplasmic Ca2+ concentration ([Ca2+]i) by endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+-release channels is a universal signaling pathway that regulates numerous cell-physiological processes. Whereas much is known regarding regulation of InsP3R activity by cytoplasmic ligands and processes, its regulation by ER-luminal Ca2+ concentration ([Ca2+]ER) is poorly understood and controversial. We discovered that the InsP3R is regulated by a peripheral membrane-associated ER-luminal protein that strongly inhibits the channel in the presence of high, physiological [Ca2+]ER. The widely-expressed Ca2+-binding protein annexin A1 (ANXA1) is present in the nuclear envelope lumen and, through interaction with a luminal region of the channel, can modify high-[Ca2+]ER inhibition of InsP3R activity. Genetic knockdown of ANXA1 expression enhanced global and local elementary InsP3-mediated Ca2+ signaling events. Thus, [Ca2+]ER is a major regulator of InsP3R channel activity and InsP3R-mediated [Ca2+]i signaling in cells by controlling an interaction of the channel with a peripheral membrane-associated Ca2+-binding protein, likely ANXA1.


Subject(s)
Annexin A1/metabolism , Calcium Signaling/physiology , Calcium/metabolism , Endoplasmic Reticulum/metabolism , Inositol 1,4,5-Trisphosphate Receptors/metabolism , A549 Cells , Animals , Calcium-Binding Proteins/metabolism , Cell Line, Tumor , Cell Physiological Phenomena/physiology , Chickens , HEK293 Cells , Humans , Inositol 1,4,5-Trisphosphate/metabolism , Ion Channel Gating , Mice , Patch-Clamp Techniques , Rats
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