Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Nov;17(11):2325-2334.
doi: 10.4103/1673-5374.338990.

Interplay of SOX transcription factors and microRNAs in the brain under physiological and pathological conditions

Milena Stevanovic  1 , Danijela Stanisavljevic Ninkovic  2 , Marija Mojsin  2 , Danijela Drakulic  2 , Marija Schwirtlich  2
Affiliations
Review

Interplay of SOX transcription factors and microRNAs in the brain under physiological and pathological conditions

Milena Stevanovic et al. Neural Regen Res. 2022 Nov.

Abstract

Precise tuning of gene expression, accomplished by regulatory networks of transcription factors, epigenetic modifiers, and microRNAs, is crucial for the proper neural development and function of the brain cells. The SOX transcription factors are involved in regulating diverse cellular processes during embryonic and adult neurogenesis, such as maintaining the cell stemness, cell proliferation, cell fate decisions, and terminal differentiation into neurons and glial cells. MicroRNAs represent a class of small non-coding RNAs that play important roles in the regulation of gene expression. Together with other gene regulatory factors, microRNAs regulate different processes during neurogenesis and orchestrate the spatial and temporal expression important for neurodevelopment. The emerging data point to a complex regulatory network between SOX transcription factors and microRNAs that govern distinct cellular activities in the developing and adult brain. Deregulated SOX/microRNA interplay in signaling pathways that influence the homeostasis and plasticity in the brain has been revealed in various brain pathologies, including neurodegenerative disorders, traumatic brain injury, and cancer. Therapeutic strategies that target SOX/microRNA interplay have emerged in recent years as a promising tool to target neural tissue regeneration and enhance neurorestoration. Numerous studies have confirmed complex interactions between microRNAs and SOX-specific mRNAs regulating key features of glioblastoma. Keeping in mind the crucial roles of SOX genes and microRNAs in neural development, we focus this review on SOX/microRNAs interplay in the brain during development and adulthood in physiological and pathological conditions. Special focus was made on their interplay in brain pathologies to summarize current knowledge and highlight potential future development of molecular therapies.

Keywords: SOX/miRNA interplay; dysregulation of miRNA expression; glioblastoma; gliogenesis; glioma stem cells; ischemic stroke; neural stem cells; neural tissue regeneration; neurodegenerative diseases; neurodevelopment; neurogenesis; traumatic brain injury.

PubMed Disclaimer

Conflict of interest statement

None

Figures

Figure 1
Figure 1
The interplay between SOX TFs and miRNAs in the regulation of self-renewal or differentiation of NSCs. The interplay of SOX and miRNAs is important for differentiation of NSCs, NPCs, and OPCs to neurons or oligodendrocytes. Unpublished data based on the previously reported publications (Zhao et al., 2010; Gokey et al., 2012; Peng et al., 2012; Hoffmann et al., 2014; Stevanato and Sinden, 2014; Sathyan et al., 2015; Reiprich et al., 2017; Afrang et al., 2019; Wittstatt et al., 2020). NPC: Neural progenitor cell; NSC: Neural stem cell; OPC: oligodendrocyte progenitor cell.
Figure 2
Figure 2
The interplay between miRNAs and SOX genes in brain pathologies. We showed experimentally validated and potential miRNAs/SOX interplay in neurodegenerative disorders, traumatic brain injury, and ischemic stroke. Unpublished data based on the previously reported publications (De Felice et al., 2014; Liu et al., 2015; Zhao et al., 2015; Harrison et al., 2016; Zheng et al., 2017; Chen et al., 2019; Gong et al., 2020; Loffreda et al., 2020; Yang et al., 2021).
Figure 3
Figure 3
The effects of specific miRNAs on the key characteristics of GBM operating through modulations of SOX protein expression. Specific miRNAs operating via down-regulation of SOX expression in GBM cells and GSCs are presented. Asterisk indicates miRNAs that target SOX in GSCs. This summary is based on the previously reported publications listed in Table 3. miRNAs marked by blue letters suppress the malignant behavior of GBM cells; miRNAs marked by red letters promote the malignant behavior of GBM cells. BTB: Blood-tumor barrier; EMT: epithelial-to-mesenchymal transition; GBM: glioblastoma; GSC: glioma stem cell.
Figure 4
Figure 4
Schematic representation of miRNAs modulating SOX protein levels in GSCs. The scheme is based on the previously reported publications listed in Table 3. miRNAs marked by blue letters suppress the malignant behavior of GSCs, miRNAs marked by red letters promote the malignant behavior of GSCs. GSC: Glioma stem cell.Besides the roles of miRNAs in regulating SOX expression in GSCs, SOX2 has a reciprocal activity, regulating the expression of selected miRNAs in GSCs. Lopez-Bertoni et al. showed that SOX2, together with OCT4, induces promoter hypermethylation and silencing of a subset of miRNAs (miR-124, miR-148a, miR-17, miR-200a, miR-217, miR-296-5p, and miR-30c) by direct transactivation of the DNMT (DNA methyltransferase) promoter and consequent global DNA methylation (Lopez-Bertoni et al., 2015). In the same study, the authors revealed that miR-148a, one of the miRNAs whose expression was down-regulated by SOX2 and OCT4, inhibits GBM cell stem-like properties and their tumor-propagating potential (Lopez-Bertoni et al., 2015). Another down-regulated miRNA, miR-296-5p, directly targets HMGA1 (High mobility group AT-hook 1), which is associated with histone H1 displacement from the SOX2 promoter and inhibition of SOX2 expression (Lopez-Bertoni et al., 2016). Presented miR-296-5p-HMGA1-SOX2 axis functions as a negative regulator of the GSC phenotype (Lopez-Bertoni et al., 2016). In the study of de la Rocha et al. (2020), forced expression of SOX2 increased the expression of miR-128b and miR-425-5p in GSCs. SOX2 controls the transcriptional activity of miR-425-5p by direct binding to the promoter of this miRNA (de la Rocha et al., 2020). The authors also revealed that miR-425-5p is involved in the regulation of the proliferation and apoptosis of GSCs (de la Rocha et al., 2020). Papagiannakopoulos et al. (2012) analyzed the tumor-suppressive role of miR-128 in genetically defined primary glioma-initiating NSCs [NSCs transformed with oncogenic EGFRvIII (Epidermal growth factor receptor variant III) and lacking tumor suppressor genes, p16/p19] and revealed that miR-128 induced repression of mitogenic signaling of glioma-initiating NSCs and enhance their differentiation. miR-128 promoted differentiation of glioma-initiating NSCs by down-regulation of Nestin and SOX2 expression (Papagiannakopoulos et al., 2012).
Figure 5
Figure 5
SOX/miRNAs interplay shared between glioblastoma and other brain pathologies (traumatic brain injury, neurodegenerative diseases, and ischemic stroke). miR-21/SOX2 interplay is common for GBM and TBI, miR-124/SOX9 and miR-204/SOX4 interplay is common for GBM and NDs, while miR-145/SOX2 interplay is common for GBM and ischemic stroke. Unpublished data based on the previously reported publications (Yang et al., 2012; Ying et al., 2013; Liu et al., 2015; Harrison et al., 2016; Xu et al., 2016; Sun et al., 2017; Sakib, 2018; Zhao et al., 2018; Zhou et al., 2018a; Chen et al., 2019; Chiu et al., 2019; Qian et al., 2019; Sabelstrom et al., 2019). GBM: Glioblastoma; NDs: neurodegenerative diseases; TBI: traumatic brain injury.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Adlakha YK, Saini N. Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128. Mol Cancer. 2014;13:33. - PMC - PubMed
    1. Afrang N, Tavakoli R, Tasharrofi N, Alian A, Naderi Sohi A, Kabiri M, Fathi-Roudsari M, Soufizomorrod M, Rajaei F, Soleimani M, Kouhkan F. A critical role for miR-184 in the fate determination of oligodendrocytes. Stem Cell Res Ther. 2019;10:112. - PMC - PubMed
    1. Aloizou AM, Pateraki G, Siokas V, Mentis AA, Liampas I, Lazopoulos G, Kovatsi L, Mitsias PD, Bogdanos DP, Paterakis K, Dardiotis E. The role of MiRNA-21 in gliomas: hope for a novel therapeutic intervention? Toxicol Rep. 2020;7:1514–1530. - PMC - PubMed
    1. Amador-Arjona A, Cimadamore F, Huang CT, Wright R, Lewis S, Gage FH, Terskikh AV. SOX2 primes the epigenetic landscape in neural precursors enabling proper gene activation during hippocampal neurogenesis. Proc Natl Acad Sci U S A. 2015;112:E1936–1945. - PMC - PubMed
    1. Angelopoulou E, Paudel YN, Piperi C. miR-124 and Parkinson's disease: a biomarker with therapeutic potential. Pharmacol Res. 2019;150:104515. - PubMed