(406) AYX2 transcription factor decoy produces a long-term resolution of chronic pain following a single intrathecal injection by inhibiting the triumvirate of KLF6, 9 and 15 transcription factors

2015 ◽  
Vol 16 (4) ◽  
pp. S77
Author(s):  
J. Mamet ◽  
M. Klukinov ◽  
S. Harris ◽  
D. Manning ◽  
S. Xie ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Intrathecal Injection ◽  
Transcription Factor Decoy

scholarly journals Altered Transcription Factor Binding and Gene Bivalency in Islets of Intrauterine Growth Retarded Rats

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1435
Author(s):  
Yu-Chin Lien ◽  
Paul Zhiping Wang ◽  
Xueqing Maggie Lu ◽  
Rebecca A. Simmons
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Transcription Factor Binding ◽  
Binding Motifs ◽  
Factor Binding ◽  
Intrauterine Growth ◽  
Gene Dysregulation ◽  
Genome Wide

Intrauterine growth retardation (IUGR), which induces epigenetic modifications and permanent changes in gene expression, has been associated with the development of type 2 diabetes. Using a rat model of IUGR, we performed ChIP-Seq to identify and map genome-wide histone modifications and gene dysregulation in islets from 2- and 10-week rats. IUGR induced significant changes in the enrichment of H3K4me3, H3K27me3, and H3K27Ac marks in both 2-wk and 10-wk islets, which were correlated with expression changes of multiple genes critical for islet function in IUGR islets. ChIP-Seq analysis showed that IUGR-induced histone mark changes were enriched at critical transcription factor binding motifs, such as C/EBPs, Ets1, Bcl6, Thrb, Ebf1, Sox9, and Mitf. These transcription factors were also identified as top upstream regulators in our previously published transcriptome study. In addition, our ChIP-seq data revealed more than 1000 potential bivalent genes as identified by enrichment of both H3K4me3 and H3K27me3. The poised state of many potential bivalent genes was altered by IUGR, particularly Acod1, Fgf21, Serpina11, Cdh16, Lrrc27, and Lrrc66, key islet genes. Collectively, our findings suggest alterations of histone modification in key transcription factors and genes that may contribute to long-term gene dysregulation and an abnormal islet phenotype in IUGR rats.

scREMOTE: Using multimodal single cell data to predict regulatory gene relationships and to build a computational cell reprogramming model

2021 ◽  
Author(s):  
Andy Tran ◽  
Pengyi Yang ◽  
Jean Yee Hwa Yang ◽  
John Thomas Ormerod
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Computational Model ◽  
Single Cell ◽  
Regulatory Gene ◽  
Cell Reprogramming ◽  
Holistic View ◽  
Long Term Effect ◽  
Hair Follicle Development

Cell reprogramming offers a potential treatment to many diseases, by regenerating specialized somatic cells. Despite decades of research, discovering the transcription factors that promote cell reprogramming has largely been accomplished through trial and error, a time-consuming and costly method. A computational model for cell reprogramming, however, could guide the hypothesis formulation and experimental validation, to efficiently utilize time and resources. Current methods often cannot account for the heterogeneity observed in cell reprogramming, or they only make short-term predictions, without modelling the entire reprogramming process. Here, we present scREMOTE, a novel computational model for cell reprogramming that leverages single cell multiomics data, enabling a more holistic view of the regulatory mechanisms at cellular resolution. This is achieved by first identifying the regulatory potential of each transcription factor and gene to uncover regulatory relationships, then a regression model is built to estimate the effect of transcription factor perturbations. We show that scREMOTE successfully predicts the long-term effect of overexpressing two key transcription factors in hair follicle development by capturing higher-order gene regulations. Together, this demonstrates that integrating the multimodal processes governing gene regulation creates a more accurate model for cell reprogramming with significant potential to accelerate research in regenerative medicine.

scholarly journals Intrathecal administration of AYX2 DNA decoy produces a long-term pain treatment in rat models of chronic pain by inhibiting the KLF6, KLF9, and KLF15 transcription factors

2017 ◽  
Vol 13 ◽  
pp. 174480691772791 ◽  
Author(s):  
Julien Mamet ◽  
Michael Klukinov ◽  
Scott Harris ◽  
Donald C Manning ◽  
Simon Xie ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Transcription Factors ◽  
Pain Treatment ◽  
Intrathecal Administration ◽  
Rat Models

scholarly journals Transcription Factor Decoy (TFD) in Breast Cancer Research and Treatment

2002 ◽  
Vol 1 (5) ◽  
pp. 405-416 ◽  
Author(s):  
Roberta Piva ◽  
Roberto Gambari
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Binding Sites ◽  
Estrogen Receptor Α ◽  
Tumor Onset ◽  
Transcription Factor Decoy ◽  
Modulation Of Gene Expression ◽  
Synthetic Oligonucleotides

Synthetic oligonucleotides have recently been the object of many investigations aimed to develop sequence-selective compounds able to modulate, either positively or negatively, transcription of eukaryotic and viral genes. Alteration of transcription could be obtained by using synthetic oligonucleotides mimicking target sites of transcription factors (the transcription factor decoy -TFD- approach). This could lead to either inhibition or activation of gene expression, depending on the biological functions of the target transcription factors. Since several transcription factors are involved in tumor onset and progression, this issue is of great interest in order to design anti-tumor compounds. In addition to oligonucleotides, peptide nucleic acids (PNA) can be proposed for the modulation of gene expression. In this respect, double-stranded PNA-DNA chimeras have been shown to be capable to exhibit strong decoy activity. In the case of treatment of breast cancer cells, decoy oligonucleotides mimicking CRE binding sites, promoter region of estrogen receptor α gene, NF-kB binding sites have been used with promising results. Therefore, the transcription factor decoy approach could be object of further studies to develop protocols for the treatment of breast cancer. In the future, transcription factors regulating cell cycle, hormone-dependent differentiation, tumor invasion and metastasis are expected to be suitable targets for transcription factor decoy.

scholarly journals PKA-activated ApAF–ApC/EBP heterodimer is a key downstream effector of ApCREB and is necessary and sufficient for the consolidation of long-term facilitation

2006 ◽  
Vol 174 (6) ◽  
pp. 827-838 ◽  
Author(s):  
Jin-A Lee ◽  
Sue-Hyun Lee ◽  
Changhoon Lee ◽  
Deok-Jin Chang ◽  
Yong Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Long Term Memory ◽  
Term Memory ◽  
Downstream Effector ◽  
Necessary And Sufficient ◽  
Long Term Facilitation

Long-term memory requires transcriptional regulation by a combination of positive and negative transcription factors. Aplysia activating factor (ApAF) is known to be a positive transcription factor that forms heterodimers with ApC/EBP and ApCREB2. How these heterodimers are regulated and how they participate in the consolidation of long-term facilitation (LTF) has not, however, been characterized. We found that the functional activation of ApAF required phosphorylation of ApAF by PKA on Ser-266. In addition, ApAF lowered the threshold of LTF by forming a heterodimer with ApCREB2. Moreover, once activated by PKA, the ApAF–ApC/EBP heterodimer transactivates enhancer response element–containing genes and can induce LTF in the absence of CRE- and CREB-mediated gene expression. Collectively, these results suggest that PKA-activated ApAF–ApC/EBP heterodimer is a core downstream effector of ApCREB in the consolidation of LTF.

scholarly journals Single intrathecal administration of the transcription factor decoy AYX1 prevents acute and chronic pain after incisional, inflammatory, or neuropathic injury

Pain ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 322-333 ◽  
Author(s):  
Julien Mamet ◽  
Michael Klukinov ◽  
Tony L. Yaksh ◽  
Shelle A. Malkmus ◽  
Samantha Williams ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Transcription Factor ◽  
Intrathecal Administration ◽  
Transcription Factor Decoy

Opioid crisis in primary care? An audit of high-dose opioid prescribing at Bangholm GP Practice

2020 ◽  
Vol 70 (suppl 1) ◽  
pp. bjgp20X711581
Author(s):  
Charlotte Greene ◽  
Alice Pearson
Keyword(s):  
Chronic Pain ◽  
Back Pain ◽  
Practice Guidelines ◽  
Best Practice ◽  
Evidence Base ◽  
High Dose ◽  
Opioid Prescription ◽  
Opioid Prescribing ◽  
Best Practice Guidelines

BackgroundOpioids are effective analgesics for acute and palliative pain, but there is no evidence base for long-term pain relief. They also carry considerable risks such as overdose and dependence. Despite this, they are increasingly prescribed for chronic pain. In the UK, opioid prescribing more than doubled between 1998 and 2018.AimAn audit at Bangholm GP Practice to understand the scale of high-strength opioid prescribing. The aim of the audit was to find out if indications, length of prescription, discussion, and documentation at initial consultation and review process were consistent with best-practice guidelines.MethodA search on Scottish Therapeutics Utility for patients prescribed an average daily dose of opioid equivalent ≥50 mg morphine between 1 July 2019 and 1 October 2019, excluding methadone, cancer pain, or palliative prescriptions. The Faculty of Pain Medicine’s best-practice guidelines were used.ResultsDemographics: 60 patients (37 females), average age 62, 28% registered with repeat opioid prescription, 38% comorbid depression. Length of prescription: average 6 years, 57% >5 years, 22% >10 years. Opioid: 52% tramadol, 23% on two opioids. Indications: back pain (42%), osteoarthritis (12%), fibromyalgia (10%). Initial consultation: 7% agreed outcomes, 35% follow-up documented. Review: 56% 4-week, 70% past year.ConclusionOpioid prescribing guidelines are not followed. The significant issues are: long-term prescriptions for chronic pain, especially back pain; new patients registering with repeat prescriptions; and no outcomes of treatment agreed, a crucial message is the goal is pain management rather than relief. Changes have been introduced at the practice: a patient information sheet, compulsory 1-month review for new patients on opioids, and in-surgery pain referrals.

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