The imbalance between transforming growth factor β and bone morphogenetic protein 7 signaling pathways is a critical step in promoting hepatic stellate cell activation during hepatic fibrogenesis. Gremlin1 may impair the balance. Something remains unclear about the regulatory mechanisms of gremlin1 action on hepatic stellate cell activation and hepatic fibrosis. In the current study, gremlin1 overexpression promotes activation of hepatic stellate cells. Knockdown of gremlin1 with siRNAs suppresses hepatic stellate cell activation and attenuates hepatic fibrosis in rat model. Our results also show that miR-23b/27b cluster members bind to 3′-untranslated region of gremlin1 resulting in reduction of transforming growth factor β, α-smooth muscle actin and collagenI α1/2 gene expression. Our findings suggest that gremlin1 promotes hepatic stellate cell activation and hepatic fibrogenesis through impairment of the balance between transforming growth factor β and bone morphogenetic protein 7 signaling pathways. The miR-23b/27b cluster suppresses activation of hepatic stellate cells through binding gremlin1 to rectify the imbalance.

Gremlin1, the antagonist of bone morphogenetic protein-7 and one of the target genes of transforming growth factor (TGF)-β signal pathway, plays an important role in embryonic development and its expression decreases along with aging. To explore the expression of gremlin1 in liver fibrosis and the causal link between gremlin1 and hepatic stellate cell (HSC) activation, we detected the expression of gremlin1 in mice with hepatic fibrosis induced by porcine serum using real time quantitative PCR (RT-qPCR) and immunohistochemical staining. The hepatic fibrosis mice were evaluated by the external feature of the liver, histology, hepatic function, collagen deposition, and the expression of fibrosis-related genes (genes COLIα2 and COLIVα2) in the liver. In the HSC-T6, western blotting was used to analyze the expression of α-smooth muscle actin (α-SMA), COL1α, and TGF-β1 in conditions of overexpression of gremlin1 or gremlin1 being knocked down by specific siRNA, respectively. The results showed that the mRNA expression of the gremlin1 gene was significantly increased consistent with increased expression of COLIα2 and COLIVα2 in the liver tissue of the hepatic fibrosis mice. Increased expression of gremlin1 coincided with the same area of the collagen deposition. Furthermore, the results also showed that the expression of α-SMA, COLIα1, and TGF-β1 was consistent with the expression of gremlin1 not only in the HSC-T6 overexpressing gremlin1 but also in the HSC-T6 that gremlin1 is knocked down by specific siRNA. The findings suggest that gremlin1 might play an important role in the progression of hepatic fibrosis and that it modulates HSC activation.

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E proteins are transcriptional regulators that regulate many developmental processes in animals and lymphocytosis and leukemia in Homo sapiens. In particular, E2A, a member of the E protein family, plays a major role in the transcriptional regulatory network that promotes the differentiation and development of B and T lymphocytes. E2A-mediated transcriptional regulation usually requires the formation of E2A dimers, which then bind to coregulators. In this review, we summarize the mechanisms by which E2A participates in transcriptional regulation from a structural perspective. More specifically, the C-terminal helix-loop-helix (HLH) region of the basic HLH (bHLH) domain first dimerizes, and then the activation domains of E2A bind to different coactivators or corepressors in different cell contexts, resulting in histone acetylation or deacetylation, respectively. Then, the N-terminal basic region (b) of the bHLH domain binds to or dissociates from a specific DNA motif (E-box sequence). Last, trans-activation or trans-repression occurs. We also summarize the properties of these E2A domains and their interactions with the domains of other proteins. The feasibility of developing drugs based on these domains is discussed.

Hepatic fibrosis is a reversible process involving plenty of transcription factors and pathways. Vitamin D receptor (VDR) as a member of ligand-induced transcription factors can interact with 9-cis retinoid X receptor (RXR) and VDR-interacting repressor (VDIR) to mediate transactivation or transrepression in the absence or in the presence of VDR ligand to regulate the expression of VDR target genes. The active form of vitamin D [1α,25(OH)2D3] can downregulate the expression of type I collagen both α1 and α2 (COLIα1 and COLIα2) in hepatic stellate cells (HSC-T6) in a time-dependent fashion, which provides a new direction for hepatic fibrosis therapy. As one of VDR target genes, rat COLIα1 gene contains 1αnVDRE (E-box1 and E-box2) in its promoter, and unliganded VDR/RXR may bind to 1αnVDRE through VDIR to mediate transactivation, whereas liganded VDR/RXR may bind to 1αnVDRE through VDIR for transrepression. The results suggested a sort of relying on each other relationship between VDR/RXR and VDIR in regulating the expression of COLIα1 gene in HSC-T6 cells, which established VDR as a potential target for blocking and even reversing hepatic fibrosis.

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OCT4 is a major transcription factor that maintains the pluripotency of stem cells, including embryonic stem cells, induced pluripotent stem cells and cancer stem cells. An increasing number of long noncoding RNAs have been reported to participate in the regulation of OCT4 expression through various mechanisms, including binding with the OCT4 gene promoter to regulate local methylation; promoting chromosomal spatial folding to form an inner ring, thereby aggregating OCT4 cis-acting elements scattered in discontinuous sites of the chromosome; competitively binding microRNAs with OCT4 to upregulate OCT4 expression at the posttranscriptional level; and sharing a promoter with OCT4. Moreover, the transcription of some long noncoding RNAs is regulated by OCT4, and certain long noncoding RNAs form feedback regulatory loops with OCT4. In this review, we summarized the research progress of the long noncoding RNAs involved in the regulation of OCT4 expression.

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