The role of transcriptional and epigenetic modifications in astrogliogenesis

Abstract

Astrocytes are widely distributed and play a critical role in the central nervous system (CNS) of the human brain. During the development of CNS, astrocytes provide essential nutritional and supportive functions for neural cells and are involved in their metabolism and pathological processes. Despite the numerous studies that have reported on the regulation of astrogliogenesis at the transcriptional and epigenetic levels, there is a paucity of literature that provides a comprehensive summary of the key factors influencing this process. In this review, we analyzed the impact of transcription factors (e.g., NFI, JAK/STAT, BMP, and Ngn2), DNA methylation, histone acetylation, and noncoding RNA on astrocyte behavior and the regulation of astrogliogenesis, hope it enhances our comprehension of the mechanisms underlying astrogliogenesis and offers a theoretical foundation for the treatment of patients with neurological diseases.

Keywords: Astrocyte; Astrogliogenesis; DNA methylation; Histone; Transcription factor.

Figure 1. Neural stem cells can differentiate into astrocytes under BMP2-induction.

Briefly, BMP2 promotes p-Smad1/5/8 getting into nuclei in the presence of YAP and activates RhoA assisted by neogenin. Ultimately, BMP2 accelerates astrocyte differentiation without the cooperation of p-Smad1/5/8 signaling and YAP signaling (modified from Huang & Xiong, 2016: Fig. 1).

Figure 2. Ngn2 and Ngn1 participate in the astrogliogenesis.

(A) WNT/ β-catenin promotes Ngn2 expression by binding to the promoter of Ngn2 via putative TCF/LEF binding sites. Next, increased Ngn2 inhibits astrocytic gene Fgfr3 and Gfap transcription by binding to their promoters, leading to restriction of astrogliogenesis. (B) Ngn1 activates miR-9 expression via promoting its transcription, and mature miR-9 decreases the expression of JAK/STAT upstream molecules, such as LIFR- β, gp130, and Jak1, by binding to their 3′ UTR. ultimately leading to inhibition of astrogliogenesis (modified from Huang & Xiong, 2016: Fig. 1).

Figure 3. Astrocytic gene regulation in astrocyte generation.

MiR-153 inhibits NFIA expression at the transcriptional level and impedes NFIA binds to the distal promoter of GFAP. The activation of STAT3 promotes the hypomethylation of the GFAP promoter. SOX9 directly binding to the GFAP promoter activates GFAP expression and it also can cooperate with NFIA or STAT3 affecting GFAP expression. FGF2 facilitates STAT/CBP complex accessing to GFAP promoter by increasing the level of H3K4me3 in STAT binding sites and inhibiting the level of H3K9me3. HDAC genes compete with the STAT/CBP complex on p300.