PARP-1 and YY1 Are Important Novel Regulators of CXCL12 Gene Transcription in Rat Pancreatic Beta Cells

Abstract

Despite significant progress, the molecular mechanisms responsible for pancreatic beta cell depletion and development of diabetes remain poorly defined. At present, there is no preventive measure against diabetes. The positive impact of CXCL12 expression on the pancreatic beta cell prosurvival phenotype initiated this study. Our aim was to provide novel insight into the regulation of rat CXCL12 gene (Cxcl12) transcription. The roles of poly(ADP-ribose) polymerase-1 (PARP-1) and transcription factor Yin Yang 1 (YY1) in Cxcl12 transcription were studied by examining their in vitro and in vivo binding affinities for the Cxcl12 promoter in a pancreatic beta cell line by the electrophoretic mobility shift assay and chromatin immunoprecipitation. The regulatory activities of PARP-1 and YY1 were assessed in transfection experiments using a reporter vector with a Cxcl12 promoter sequence driving luciferase gene expression. Experimental evidence for PARP-1 and YY1 revealed their trans-acting potential, wherein PARP-1 displayed an inhibitory, and YY1 a strong activating effect on Cxcl12 transcription. Streptozotocin (STZ)-induced general toxicity in pancreatic beta cells was followed by changes in Cxcl12 promoter regulation. PARP-1 binding to the Cxcl12 promoter during basal and in STZ-compromised conditions led us to conclude that PARP-1 regulates constitutive Cxcl12 expression. During the early stage of oxidative stress, YY1 exhibited less affinity toward the Cxcl12 promoter while PARP-1 displayed strong binding. These interactions were accompanied by Cxcl12 downregulation. In the later stages of oxidative stress and intensive pancreatic beta cell injury, YY1 was highly expressed and firmly bound to Cxcl12 promoter in contrast to PARP-1. These interactions resulted in higher Cxcl12 expression. The observed ability of PARP-1 to downregulate, and of YY1 to upregulate Cxcl12 promoter activity anticipates corresponding effects in the natural context where the functional interplay of these proteins could finely balance Cxcl12 transcription.

Absence of PARP‐1 affects Cxcl12 expression by increasing DNA demethylation

“…Our previous results based on transfection experiments revealed that PARP‐1 plays a role in suppression of the Cxcl12 promoter . Findings presented herein strongly support an inhibitory role of PARP‐1 in the regulation of Cxcl12 gene expression.…”

Protective Effects of the MushroomLactarius deterrimusExtract on Systemic Oxidative Stress and Pancreatic Islets in Streptozotocin-Induced Diabetic Rats

“…The chemokine CXCL12 and its receptor, CXCR4, have been shown to mediate β -cell repair [ 28 ]. Immunohistochemical staining revealed the presence of CXCL12-positive cells only in diabetic islets and their increased presence in islets from Ld-treated rats.…”

A data-driven drug repositioning framework discovered a potential therapeutic agent targeting COVID-19

“…Second, PARP1 inhibitors have been previously reported to play a critical role in regulating inflammatory response by modulating the expression of pro-inflammatory factors such as NF-κB, AP-1, IL-6 and downstream cytokines and chemokines [37,38,39,40]. Also, it has been shown that the overactivation of PARP1 promotes energy (NAD + /ATP) consumption and drives cell death, exacerbating the inflammation response [37,38,39,41]. PARP1 inhibitors thus may repress the NF-κB-mediated pro-inflammatory signals, and reduce energy failure and subsequent cell death induced by necrosis, thus providing a clinical potential for attenuating the cytokine storm and inflammatory response caused by SARS-CoV-2 infection.…”