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Nuc-ErbB3, an alternative transcript from the ErbB3 locus, binds to a specific DNA motif and associates with Schwann cell chromatin. Here we generated a nuc-ErbB3 knockin mouse that lacks nuc-ErbB3 expression in the nucleus without affecting the neuregulin-ErbB3 receptor signaling. Nuc-ErbB3 knockin mice exhibit hypermyelination and aberrant myelination at the paranodal region. This phenotype is attributed to de-repression of myelination associated gene transcription following loss of nuc-ErbB3 and histone H3K27me3 promoter occupancy. Nuc-ErbB3 knockin mice exhibit reduced association of H3K27me3 with myelination-associated gene promoters and increased RNA Pol-II rate of transcription of these genes. In addition, nuc-ErbB3 directly regulates levels of H3K27me3 in Schwann cells. Nuc-ErbB3 knockin mice exhibit significant decrease of histone H3K27me3 methyltransferase (HMT) activity and reduced levels of H3K27me3. Collectively, nuc-ErbB3 is a master transcriptional repressor, which regulates HMT activity to establish a repressive chromatin landscape on promoters of genes during peripheral myelination.
A pre-clinical animal model of chronic ligation of the sciatic nerve was used to compare the effectiveness of a slow-release hydrogelcarrying methylprednisolone to methylprednisolone injection alone, which simulates the current standard of care for chronic compressiveradiculopathy (CR).
To extend the short-term benefits of steroid injections by using a non-swelling, biodegradable hydrogel as carrier to locally releasemethylprednisolone in a regulated and sustained way at the site of nerve compression.
SUMMARY OF BACKGROUND DATA:
CR affects millions worldwide annually, and is a cause of costly disability with significant societal impact. Currently, a leading non-surgical therapy involves epidural injection of steroids to temporarily alleviate the pain associated with CR. However, an effective way to extend the short-term effect of steroid treatment to addresses the chronic component of CR does not exist.
We induced chronic compression injury of the sciatic nerves of rats by permanent ligation. 48 hours later we injected ourmethylprednisolone infused hydrogel and assessed the effectiveness of our treatment for four weeks. We quantified mechanical hyperalgesia using a Dynamic Plantar Aesthesiometer (Ugo Basile), while gait analysis was conducted using the Catwalk automated gait analysis platform (Noldus). Macrophage staining was performed with immunohistochemistry and quantification of MCP-1 in sciatic nerve lysates was performed with multiplex immunoassay using a SECTOR Imager 2400A (Meso Scale Discovery).
We demonstrate that using the hydrogel to deliver methylprednisolone results in significant (p < 0.05) reduction of hyperalgesia and improvement in the gait pattern of animals with chronic lesions as compared to animals treated with steroid alone. In addition, animals treated withhydrogel plus steroid showed significant reduction in the number of infiltrating macrophages at the sciatic nerve and reduced expression of the neuro-inflammatory chemokine MCP-1 (p < 0.05).
Use of hydrogels as carriers for sustained local release of steroids provides significantly better control of pain in an animal model of chronic CR. Our steroid-infused hydrogel could be an effective extender of the short-term benefits of epidural steroid injections for patients with chronic compression-induced radicular pain.
Proper cell functioning depends on the precise spatio-temporal expression of its genetic material. Gene expression is controlled to a great extent by sequence-specific transcription factors (TFs). Our current knowledge on where and how TFs bind and associate to regulate gene expression is incomplete. A structure-based computational algorithm (TF2DNA) is developed to identify binding specificities of TFs. The method constructs homology models of TFs bound to DNA and assesses the relative binding affinity for all possible DNA sequences using a knowledge-based potential, after optimization in a molecular mechanics force field. TF2DNA predictions were benchmarked against experimentally determined binding motifs. Success rates range from 45% to 81% and primarily depend on the sequence identity of aligned target sequences and template structures, TF2DNA was used to predict 1321 motifs for 1825 putative human TF proteins, facilitating the reconstruction of most of the human gene regulatory network. As an illustration, the predicted DNA binding site for the poorly characterized T-cell leukemia homeobox 3 (TLX3) TF was confirmed with gel shift assay experiments. TLX3 motif searches in human promoter regions identified a group of genes enriched in functions relating to hematopoiesis, tissue morphology, endocrine system and connective tissue development and function.
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