scholarly journals Noncatalytic Function of a JmjC Domain Protein Disrupts Heterochromatin

2019 ◽  
Vol 12 ◽  
pp. 251686571986224
Author(s):  
Kehan Bao ◽  
Songtao Jia
Keyword(s):  
Transcriptional Regulation ◽  
Cancer Cells ◽  
Histone Acetyltransferase ◽  
Histone Demethylase ◽  
Epigenetic Landscape ◽  
Disease Etiology ◽  
Chromatin Regulators ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Domain Protein

Chromatin-modifying enzymes are frequently overexpressed in cancer cells, and their enzymatic activities play important roles in changing the epigenetic landscape responsible for tumorigenesis. However, many of these proteins also execute noncatalytic functions, which are poorly understood. In fission yeast, overexpression of Epe1, a histone demethylase homolog, causes heterochromatin defects. Interestingly, in our recent work, we discovered that overexpressed Epe1 recruits SAGA, a histone acetyltransferase complex important for transcriptional regulation, to disrupt heterochromatin, independent of its demethylase activity. Our findings suggest that overexpressed chromatin-modifying enzymes can alter the epigenetic landscape through changing their proteomic environments, an area that needs to be further explored in dissecting disease etiology associated with overexpression of chromatin regulators.

JmjN interacts with JmjC to ensure selective proteolysis of Gis1 by the proteasome

Microbiology ◽  
2011 ◽  
Vol 157 (9) ◽  
pp. 2694-2701 ◽  
Author(s):  
Zhenzhen Quan ◽  
Stephen G. Oliver ◽  
Nianshu Zhang
Keyword(s):  
Structural Unit ◽  
Transcription Activation ◽  
Histone Demethylase ◽  
Transcription Activity ◽  
The Core ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Β Sheets ◽  
The Stability ◽  
Selective Proteolysis

A group of JmjC domain-containing proteins also harbour JmjN domains. Although the JmjC domain is known to possess histone demethylase activity, the function of the JmjN domain remains largely undetermined. Previously, we have demonstrated that the yeast Gis1 transcription factor, bearing both JmjN and JmjC domains at its N terminus, is subject to proteasome-mediated selective proteolysis to downregulate its transcription activation ability. Here, we reveal that the JmjN and JmjC domains interact with each other through two β-sheets, one in each domain. Removal of either or both β-strands or the entire JmjN domain leads to complete degradation of Gis1, mediated partially by the proteasome. Mutating the core residues essential for histone demethylase activity demonstrated for other JmjC-containing proteins or deleting both Jumonji domains enhances the transcription activity of Gis1, but has no impact on its selective proteolysis by the proteasome. Together, these data suggest that JmjN and JmjC interact physically to form a structural unit that ensures the stability and appropriate transcription activity of Gis1.

scholarly journals Heme, A Metabolic Sensor, Directly Regulates the Activity of the KDM4 Histone Demethylase Family and Their Interactions with Partner Proteins

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 773
Author(s):  
Purna Chaitanya Konduri ◽  
Tianyuan Wang ◽  
Narges Salamat ◽  
Li Zhang
Keyword(s):  
Histone Demethylase ◽  
Interacting Proteins ◽  
Cellular Functions ◽  
Functional Activities ◽  
Nutritional Conditions ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Metabolic Sensor ◽  
Heme Regulation ◽  
Partner Proteins

The KDM4 histone demethylase subfamily is constituted of yeast JmjC domain-containing proteins, such as Gis1, and human Gis1 orthologues, such as KDM4A/B/C. KDM4 proteins have important functions in regulating chromatin structure and gene expression in response to metabolic and nutritional stimuli. Heme acts as a versatile signaling molecule to regulate important cellular functions in diverse organisms ranging from bacteria to humans. Here, using purified KDM4 proteins containing the JmjN/C domain, we showed that heme stimulates the histone demethylase activity of the JmjN/C domains of KDM4A and Cas well as full-length Gis1. Furthermore, we found that the C-terminal regions of KDM4 proteins, like that of Gis1, can confer heme regulation when fused to an unrelated transcriptional activator. Interestingly, biochemical pull-down of Gis1-interacting proteins followed by mass spectrometry identified 147 unique proteins associated with Gis1 under heme-sufficient and/or heme-deficient conditions. These 147 proteins included a significant number of heterocyclic compound-binding proteins, Ubl-conjugated proteins, metabolic enzymes/proteins, and acetylated proteins. These results suggested that KDM4s interact with diverse cellular proteins to form a complex network to sense metabolic and nutritional conditions like heme levels and respond by altering their interactions with other proteins and functional activities, such as histone demethylation.

PLU1 histone demethylase decreases the expression of KAT5 and enhances the invasive activity of the cells

2011 ◽  
Vol 437 (3) ◽  
pp. 555-564 ◽  
Author(s):  
Masakazu Yoshida ◽  
Akihiko Ishimura ◽  
Minoru Terashima ◽  
Zanabazar Enkhbaatar ◽  
Naohito Nozaki ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Progression ◽  
Cell Invasion ◽  
Histone H3 ◽  
Ectopic Expression ◽  
Histone Demethylase ◽  
Invasive Cancer ◽  
Invasive Potential ◽  
Demethylase Activity ◽  
Candidate Oncogene

PLU1 is a candidate oncogene that encodes H3K4 (Lys4 of histone H3) demethylase. In the present study, we found that ectopic expression of PLU1 enhanced the invasive potential of the weakly invasive cells dependent on its demethylase activity. PLU1 was shown to repress the expression of the KAT5 gene through its H3K4 demethylation on the promoter. The regulation of KAT5 by PLU1 was suggested to be responsible for PLU1-induced cell invasion. First, knockdown of KAT5 similarly increased the invasive potential of the cells. Secondly, knockdown of PLU1 in the highly invasive cancer cells increased KAT5 expression and reduced the invasive activity. Thirdly, simultaneous knockdown of KAT5 partially relieved the suppression of cell invasion imposed by PLU1 knockdown. Finally, we found that CD82, which was transcriptionally regulated by KAT5, might be a candidate effector of cell invasion promoted by PLU1. The present study demonstrated a functional contribution of PLU1 overexpression with concomitant epigenetic dysregulation in cancer progression.

Crystal structure of the catalytic core of Saccharomyces cerevesiae histone demethylase Rph1: insights into the substrate specificity and catalytic mechanism

2010 ◽  
Vol 433 (2) ◽  
pp. 295-302 ◽  
Author(s):  
Yuanyuan Chang ◽  
Jian Wu ◽  
Xia-Jing Tong ◽  
Jin-Qiu Zhou ◽  
Jianping Ding
Keyword(s):  
Substrate Specificity ◽  
Substrate Binding ◽  
Histone Demethylase ◽  
Structural Motif ◽  
Catalytic Core ◽  
Conserved Residues ◽  
Demethylase Activity ◽  
Jmjc Domain ◽  
Saccharomyces Cerevesiae ◽  
Binding Cleft

Saccharomyces cerevesiae Rph1 is a histone demethylase orthologous to human JMJD2A (Jumonji-domain-containing protein 2A) that can specifically demethylate tri- and di-methylated Lys36 of histone H3. c-Rph1, the catalytic core of Rph1, is responsible for the demethylase activity, which is essential for the transcription elongation of some actively transcribed genes. In the present work, we report the crystal structures of c-Rph1 in apo form and in complex with Ni2+ and α-KG [2-oxoglutarate (α-ketoglutarate)]. The structure of c-Rph1 is composed of a JmjN (Jumonji N) domain, a long β-hairpin, a mixed structural motif and a JmjC domain. The α-KG cofactor forms hydrogen-bonding interactions with the side chains of conserved residues, and the Ni2+ ion at the active site is chelated by conserved residues and the cofactor. Structural comparison of Rph1 with JMJD2A indicates that the substrate-binding cleft of Rph1 is formed with several structural elements of the JmjC domain, the long β-hairpin and the mixed structural motif; and the methylated Lys36 of H3 is recognized by several conserved residues of the JmjC domain. In vitro biochemical results show that mutations of the key residues at the catalytic centre and in the substrate-binding cleft abolish the demethylase activity. In vivo growth phenotype analyses also demonstrate that these residues are essential for its functional roles in transcription elongation. Taken together, our structural and biological data provide insights into the molecular basis of the histone demethylase activity and the substrate specificity of Rph1.

scholarly journals Rapid epigenetic adaptation to uncontrolled heterochromatin spreading

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Jiyong Wang ◽  
Bharat D Reddy ◽  
Songtao Jia
Keyword(s):  
Protein Binding ◽  
Fission Yeast ◽  
Histone Acetyltransferase ◽  
H3k9 Methylation ◽  
Growth Defects ◽  
Adaptation Response ◽  
Jmjc Domain ◽  
Domain Protein ◽  
Heterochromatin Assembly ◽  
Severe Growth

Heterochromatin, a highly compact chromatin state characterized by histone H3K9 methylation and HP1 protein binding, silences the underlying DNA and influences the expression of neighboring genes. However, the mechanisms that regulate heterochromatin spreading are not well understood. In this study, we show that the conserved Mst2 histone acetyltransferase complex in fission yeast regulates histone turnover at heterochromatin regions to control heterochromatin spreading and prevents ectopic heterochromatin assembly. The combined loss of Mst2 and the JmjC domain protein Epe1 results in uncontrolled heterochromatin spreading and massive ectopic heterochromatin, leading to severe growth defects due to the inactivation of essential genes. Interestingly, these cells quickly recover by accumulating heterochromatin at genes essential for heterochromatin assembly, leading to their reduced expression to restrain heterochromatin spreading. Our studies discover redundant pathways that control heterochromatin spreading and prevent ectopic heterochromatin assembly and reveal a fast epigenetic adaptation response to changes in heterochromatin landscape.

scholarly journals The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

2019 ◽  
Author(s):  
Abhishek A. Chakraborty ◽  
Tuomas Laukka ◽  
Matti Myllykoski ◽  
Alison E. Ringel ◽  
Matthew A. Booker ◽  
...  
Keyword(s):  
Cell Fate ◽  
Indirect Effects ◽  
Mammalian Cells ◽  
Control Cell ◽  
Histone Demethylase ◽  
Hypoxic Induction ◽  
Hypoxic Conditions ◽  
Chromatin Regulators ◽  
Oxygen Sensitive ◽  
Demethylase Activity

AbstractMammalian cells express multiple 2-oxoglutarate (OG)-dependent dioxygenases, including many chromatin regulators. The oxygen affinities, and hence oxygen sensing capabilities, of the 2-oxoglutarate (OG)-dependent dioxygenases reported to date vary widely. Hypoxia can affect chromatin, but whether this reflects a direct effect on chromatin-modifying dioxygenases, or indirect effects caused by the hypoxic-induction of the HIF transcription factor or the endogenous 2-OG competitor 2-hydroxyglutarate (2-HG), is unclear. Here we report that hypoxia induces a HIF- and 2-HG-independent histone modification signature consistent with KDM inactivation. We also show that the H3K27 histone demethylase KDM6A (also called UTX), but not its paralog KDM6B, is oxygen-sensitive. KDM6A loss, like hypoxia, prevented H3K27me3 erasure and blocked differentiation. Conversely, restoring H3K27me3 homeostasis in hypoxic cells reversed these effects. Therefore, oxygen directly affects chromatin regulators to control cell fate.One Sentence SummaryKDM6A demethylase activity is diminished under hypoxic conditions and causes changes in gene expression programs that govern cell fate.

Structure of the JmjC-domain-containing protein JMJD5

2013 ◽  
Vol 69 (10) ◽  
pp. 1911-1920 ◽  
Author(s):  
Haipeng Wang ◽  
Xing Zhou ◽  
Minhao Wu ◽  
Chengliang Wang ◽  
Xiaoqin Zhang ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Embryonic Cell ◽  
Histone Demethylase ◽  
Amino Acid Residues ◽  
Lysine Methylation ◽  
Post Translational Modification ◽  
Active Centre ◽  
Histone Tails ◽  
Demethylase Activity ◽  
Jmjc Domain

The post-translational modification of histone tails is the principal process controlling epigenetic regulation in eukaryotes. The lysine methylation of histones is dynamically regulated by two distinct classes of enzymes: methyltransferases and demethylases. JMJD5, which plays an important role in cell-cycle progression, circadian rhythms and embryonic cell proliferation, has been shown to be a JmjC-domain-containing histone demethylase with enzymatic activity towards H3K36me2. Here, the crystal structure of human JMJD5 lacking the N-terminal 175 amino-acid residues is reported. The structure showed that the Gln275, Trp310 and Trp414 side chains might block the insertion of methylated lysine into the active centre of JMJD5, suppressing the histone demethylase activity of the truncated JMJD5 construct. A comparison of the structure of JMJD5 with that of FIH, a well characterized protein hydroxylase, revealed that human JMJD5 might function as a protein hydroxylase. The interaction between JMJD5 and the core histone octamer proteins indicated that the histone proteins could be potential substrates for JMJD5.

scholarly journals Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

2021 ◽  
Vol 7 (9) ◽  
pp. eabd7974
Author(s):  
Michela Serresi ◽  
Sonia Kertalli ◽  
Lifei Li ◽  
Matthias Jürgen Schmitt ◽  
Yuliia Dramaretska ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Transcriptional Control ◽  
Molecular Mechanisms ◽  
Developmental Process ◽  
Epithelial Mesenchymal Transition ◽  
Chromatin Remodelers ◽  
Mesenchymal Transition ◽  
Signature Genes ◽  
Chromatin Regulators ◽  
The Impact

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

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