Comprehensive Analysis of Jumonji Domain C Family from Citrus grandis and Expression Profilings in the Exocarps of “Huajuhong” (Citrus grandis “Tomentosa”) during Various Development Stages

Citrus grandis “Tomentosa” (“Huajuhong”) is a famous Traditional Chinese Medicine. In this study, a total of 18 jumonji C (JMJC) domain-containing proteins were identified from C. grandis. The 18 CgJMJCs were unevenly located on six chromosomes of C. grandis. Phylogenetic analysis revealed that they could be classified into five groups, namely KDM3, KDM4, KDM5, JMJC, and JMJD6. The domain structures and motif architectures in the five groups were diversified. Cis-acting elements on the promoters of 18 CgJMJC genes were also investigated, and the abscisic acid-responsive element (ABRE) was distributed on 15 CgJMJC genes. Furthermore, the expression profiles of 18 CgJMJCs members in the exocarps of three varieties of “Huajuhong”, for different developmental stages, were examined. The results were validated by quantitative real-time PCR (qRT-PCR). The present study provides a comprehensive characterization of JMJC domain-containing proteins in C. grandis and their expression patterns in the exocarps of C. grandis “Tomentosa” for three varieties with various development stages.

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting.

Genome-wide identification, classification and expression analysis of the JmjC domain-containing histone demethylase gene family in Jatropha curcas L.

JmjC domain-containing proteins, an important family of histone lysine demethylase, play significant roles in maintaining the homeostasis of histone methylation. In this study, we comprehensively analyzed the JmjC domain-containing gene family in Jatropha curcas and found 20 JmjC domain-containing genes (JcJMJ genes). Phylogenetic analysis revealed that these JcJMJ genes can be classified into five major subgroups, and genes in each subgroup had similar motif and domain composition. Cis-regulatory element analysis showed that the number and types of cis-regulatory elements owned by the promoter of JcJMJ genes in different subgroups were significantly different. Moreover, the miRNA target prediction result revealed a complicated miRNA-mediated post-transcriptional regulatory network, in which JcJMJ genes were regulated by different numbers and types of miRNAs. Further analysis of the tissue and stress expression profiles showed that many JcJMJ genes had tissue and stress expression specificity. All these results provided valuable information for understanding the evolution of JcJMJ genes and the complex transcriptional and post-transcriptional regulation involved and laid the foundation for further functional analysis of JcJMJ genes.

Characterization and Stress Response of the JmjC Domain-Containing Histone Demethylase Gene Family in the Allotetraploid Cotton Species Gossypium hirsutum

Histone modification is an important epigenetic modification that controls gene transcriptional regulation in eukaryotes. Histone methylation is accomplished by histone methyltransferase and can occur on two amino acid residues, arginine and lysine. JumonjiC (JmjC) domain-containing histone demethylase regulates gene transcription and chromatin structure by changing the methylation state of the lysine residue site and plays an important role in plant growth and development. In this study, we carried out genome-wide identification and comprehensive analysis of JmjC genes in the allotetraploid cotton species Gossypium hirsutum. In total, 50 JmjC genes were identified and in G. hirsutum, and 25 JmjC genes were identified in its two diploid progenitors, G. arboreum and G. raimondii, respectively. Phylogenetic analysis divided these JmjC genes into five subfamilies. A collinearity analysis of the two subgenomes of G. hirsutum and the genomes of G. arboreum and G. raimondii uncovered a one-to-one relationship between homologous genes of the JmjC gene family. Most homologs in the JmjC gene family between A and D subgenomes of G. hirsutum have similar exon-intron structures, which indicated that JmjC family genes were conserved after the polyploidization. All G. hirsutumJmjC genes were found to have a typical JmjC domain, and some genes also possess other special domains important for their function. Analysis of promoter regions revealed that cis-acting elements, such as those related to hormone and abiotic stress response, were enriched in G. hirsutum JmjC genes. According to a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, most G. hirsutumJmjC genes had high abundance expression at developmental stages of fibers, suggesting that they might participate in cotton fiber development. In addition, some G. hirsutumJmjC genes were found to have different degrees of response to cold or osmotic stress, thus indicating their potential role in these types of abiotic stress response. Our results provide useful information for understanding the evolutionary history and biological function of JmjC genes in cotton.

Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression

Oxygen homeostasis regulation is the most fundamental cellular process for adjusting physiological oxygen variations, and its irregularity leads to various human diseases, including cancer. Hypoxia is closely associated with cancer development, and hypoxia/oxygen-sensing signaling plays critical roles in the modulation of cancer progression. The key molecules of the hypoxia/oxygen-sensing signaling include the transcriptional regulator hypoxia-inducible factor (HIF) which widely controls oxygen responsive genes, the central members of the 2-oxoglutarate (2-OG)-dependent dioxygenases, such as prolyl hydroxylase (PHD or EglN), and an E3 ubiquitin ligase component for HIF degeneration called von Hippel–Lindau (encoding protein pVHL). In this review, we summarize the current knowledge about the canonical hypoxia signaling, HIF transcription factors, and pVHL. In addition, the role of 2-OG-dependent enzymes, such as DNA/RNA-modifying enzymes, JmjC domain-containing enzymes, and prolyl hydroxylases, in gene regulation of cancer progression, is specifically reviewed. We also discuss the therapeutic advancement of targeting hypoxia and oxygen sensing pathways in cancer.

Lysine Demethylase KDM6A in Differentiation, Development, and Cancer

ABSTRACT Lysine demethylase 6A (KDM6A), also known as UTX, belongs to the KDM6 family of histone H3 lysine 27 (H3K27) demethylases, which also includes UTY and KDM6B (JMJD3). The KDM6A protein contains six tetratricopeptide repeat (TPR) domains and an enzymatic Jumonji C (JmjC) domain that catalyzes the removal of di- and trimethylation on H3K27. KDM6A physically associates with histone H3 lysine 4 monomethyltransferases MLL3 (KMT2C) and MLL4 (KMT2D). Since its identification as an H3K27 demethylase in 2007, studies have reported KDM6A’s critical roles in cell differentiation, development, and cancer. KDM6A is important for differentiation of embryonic stem cells and development of various tissues. Mutations of KDM6A cause Kabuki syndrome. KDM6A is frequently mutated in cancers and functions as a tumor suppressor. KDM6A is redundant with UTY and functions largely independently of its demethylase activity. It regulates gene expression, likely through the associated transcription factors and MLL3/4 on enhancers. However, KDM6A enzymatic activity is required in certain cellular contexts. Functional redundancy between H3K27 demethylase activities of KDM6A and KDM6B in vivo has yet to be determined. Further understanding of KDM6A functions and working mechanisms will provide more insights into enhancer regulation and may help generate novel therapeutic approaches to treat KDM6A-related diseases.

The inhibition of KDM2B promotes the differentiation of basal-like breast cancer cells via the posttranslational destabilization of SLUG

ABSTRACTKDM2B is a JmjC domain H3K36me2/H3K36me1 demethylase, which immortalizes cells in culture and contributes to the biology of both embryonic and adult stem and progenitor cells. It also functions as an oncogene that contributes to the self-renewal of breast cancer stem cells by regulating polycomb complexes. Here we show that the silencing of KDM2B results in the downregulation of SNAI2 (SLUG), SNAI1 (SNAIL) and SOX9, which also contribute to the biology of mammary stem and progenitor cells. The downregulation of these molecules is posttranscriptional and in the case of the SNAI2-encoded SLUG, it is due to calpain-dependent proteolytic degradation. Mechanistically, the latter depends on the activation of calpastatin-sensitive classical calpain(s) and on the phosphorylation-dependent inhibition of GSK3 via paracrine mechanisms. GSK3 inhibition sensitizes its target SLUG to classical calpains, which are activated by Ca2+ influx and calpastatin downregulation. The degradation of SLUG, induced by the KDM2B knockdown, promotes the differentiation of breast cancer stem cells in culture and reveals an unexpected mechanism of stem cell regulation by a histone demethylase.