JMJD3 as an epigenetic regulator in development and disease

Abstract

Gene expression is epigenetically regulated through DNA methylation and covalent chromatin modifications, such as acetylation, phosphorylation, ubiquitination, sumoylation, and methylation of histones. Histone methylation state is dynamically regulated by different groups of histone methyltransferases and demethylases. The trimethylation of histone 3 (H3K4) at lysine 4 is usually associated with the activation of gene expression, whereas trimethylation of histone 3 at lysine 27 (H3K27) is associated with the repression of gene expression. The polycomb repressive complex contains the H3K27 methyltransferase Ezh2 and controls dimethylation and trimethylation of H3K27 (H3K27me2/3). The Jumonji domain containing-3 (Jmjd3, KDM6B) and ubiquitously transcribed X-chromosome tetratricopeptide repeat protein (UTX, KDM6A) have been identified as H3K27 demethylases that catalyze the demethylation of H3K27me2/3. The role and mechanisms of both JMJD3 and UTX have been extensively studied for their involvement in development, cell plasticity, immune system, neurodegenerative disease, and cancer. In this review, we will focus on recent progresses made on understanding JMJD3 in the regulation of gene expression in development and diseases. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.

Notch-effector CSL promotes squamous cell carcinoma by repressing histone demethylase KDM6B

“…This gene is essential for life after birth, as knockout mice are born smaller and die perinatally due to respiratory failure (21,61,62). Previous studies have pointed to a potential tumor-suppressive role of KDM6B in specific tissues (such as lung, colon, and pancreas) (30)(31)(32)63), while in others (such as blood, breast, and brain) it may play an opposite tumor-promoting function (24)(25)(26).…”

“…Targeting epigenetic regulators is emerging as promising cancer therapy. Pharmacological inhibitors of KDM6B (such as GSK-J4) (75) were shown to inhibit growth of different cancer cell lines, such as T-ALL and glioma (20,21,76,77), in which KDM6B plays an oncogenic role (22). While use of these compounds would obviously be contraindicated for squamous cancer, other drugs enhancing KDM6B function or inhibiting epigenetic modifying enzymes with an opposite role could be of benefit and open novel windows of opportunity for both prevention and treatment of this disease.…”

“…Growth inhibitory effects of CSL gene silencing were not due to specific toxic mechanisms, as they were not observed with SCCO28 cells (Figure 4, D-F), an oral SCC-derived cell line with advanced features of epithelial-to-mesenchymal transformation (48). The sphere-forming capability of various SCC cell lines in cell-cycle control, senescence, and differentiation, and may play a role in cancer development in a context-dependent manner (21)(22)(23). In fact, KDM6B expression is upregulated in several malignancies, such as Hodgkin's lymphoma (24), breast cancer (25), gliomas (26), melanoma (27), and renal cell carcinoma (28), while it is suppressed in others, including lung adenocarcinoma and squamous cell carcinoma (29), colon cancer (30,31), and liver and pancreatic cancers (32).…”

Kdm6b regulates cartilage development and homeostasis through anabolic metabolism

“…Trimethylation of H3K37 is typically associated with gene inactivation, while monomethylation of H3K27 is associated with gene activation 18 19 . Kdm6b is reported to be involved in many cellular processes, such as proliferation, differentiation, apoptosis and senescence 20. Homozygous Kdm6b -deficient newborn mice were reported to become cyanotic within minutes due to respiratory failure and died shortly with kyphosis and severe lordosis 21 .…”

Role of Serum Amyloid A, Granulocyte-Macrophage Colony-Stimulating Factor, and Bone Marrow Granulocyte-Monocyte Precursor Expansion in Segmented Filamentous Bacterium-Mediated Protection from Entamoeba histolytica

“…Our laboratory has previously observed that SFB colonization can increase serum levels of SAA (11), but this had not been explored beyond acute colonization with the bacteria. During acute colonization with SFB, serum levels of the DAMP SAA were significantly increased, as was bone marrow expression of Jmjd3, encoding an H3K27 demethylase (36). However, SAA and Jmjd3 did not remain elevated after SFB was cleared.…”