The Transcription Factor C-Myc Suppresses MiR-23b and MiR-27b Transcription during Fetal Distress and Increases the Sensitivity of Neurons to Hypoxia-Induced Apoptosis

Abstract

Previous studies reported that the expression of miR-23b-27b cluster was downregulated in embryonic brain cortices during hypoxia-induced neuronal apoptosis. However, the mechanism underlying this downregulation is not completely understood. Here, we report that the transcription factor c-Myc plays an important role in regulating the expression of miR-23b-27b cluster during hypoxia. First, the c-Myc protein level was significantly elevated in embryonic brain cortices in a mouse model of fetal distress. Second, forced overexpression or knockdown of c-Myc could suppress or increase the expression of miR-23b-27b cluster polynucleotides. Third, we identified 2 conserved c-Myc binding sites (E-boxes) in the enhancer and promoter regions of miR-23b-27b cluster in the mouse genome. Finally, we showed that elevated c-Myc expression led to an increase in the Apaf-1 level by suppressing miR-23b-27b cluster expression and that this enhanced neuronal sensitivity to apoptosis. In summary, our study demonstrates that c-Myc may suppress the expression of the miR-23b-27b cluster, resulting in additional neuronal apoptosis during hypoxia.

PDGFR-modulated miR-23b cluster and miR-125a-5p suppress lung tumorigenesis by targeting multiple components of KRAS and NF-kB pathways

“…A positive feedback mechanism mediated by p53-miR-24-MDM2 activates miR-23b cluster and miR-125a-5p expression, whereas, a NF-kB p65-mediated negative regulatory loop blocks the transcriptional activation of both miR-23b cluster and miR-125a-5p. Importantly, previous studies have reported that AP-1 and c-Myc are also able to suppress the expression of miR-23b cluster, confirming they act as “bona fide” tumor suppressor microRNAs 41 , 42 . EMT is a multistep process associated with metastasis and drug resistance.…”

MicroRNA-27b Modulates Inflammatory Response and Apoptosis duringMycobacterium tuberculosisInfection

“…Several studies have demonstrated that miR-27b plays an important role in regulating various physical and pathological process by repressing distinct targets, such as KH-type splicing regulatory protein (38) and apoptotic protease activating factor-1 (Apaf-1) (39). Most of these miR-27b targets modulate inflammatory response and apoptosis.…”

Transcriptomic changes due to early, chronic intermittent alcohol exposure during forebrain development implicate WNT signaling, cell‐type specification, and cortical regionalization as primary determinants of fetal alcohol syndrome

“…Interestingly, miR-23b expression was inversely correlated with DLX1 expression, suggesting that miR-23b may be able to downregulate DLX1 expression via posttranscriptional repression (Figure 3d). The exact function of the miR-23b-27b cluster has yet to be fully uncovered, but it has been shown to confer neuroprotective effects both in vitro and in vivo, via direct repression of apoptotic protease activating factor-1 (APAF1) specifically in neurons (Chen et al, 2014(Chen et al, , 2015Sun et al, 2018). However, in the current study, we did not find significant differences in APAF1 expression in alcohol-treated neurons (p > 0.05; FDR = 0.932), suggesting that additional miR-23b-independent mechanisms could be regulating APAF1 expression.…”