scholarly journals JARID2 and AEBP2 regulate PRC2 activity in the presence of H2A ubiquitination or other histone modifications

2020 ◽  
Author(s):  
Vignesh Kasinath ◽  
Curtis Beck ◽  
Paul Sauer ◽  
Simon Poepsel ◽  
Jennifer Kosmatka ◽  
...  
Keyword(s):  
Zinc Fingers ◽  
Regulation Of Gene Expression ◽  
Inhibitory Effect ◽  
Histone H2a ◽  
Set Domain ◽  
Methyltransferase Activity ◽  
Post Translational Modifications ◽  
Nucleosomal Dna ◽  
Polycomb Repressive Complexes ◽  
Stimulation Of

ABSTRACTThe Polycomb repressive complexes PRC1 and PRC2 functionally interact to coordinate cell type identity by the epigenetic regulation of gene expression. It has been proposed that PRC2 is recruited to genomic loci via the recognition of PRC1-mediated mono-ubiquitination of histone H2A at lysine 119 (H2AK119ub1), but the mechanism of this process remains poorly understood. Here, we report the cryo-EM structure of human PRC2 with cofactors JARID2 and AEBP2 bound to a nucleosome substrate containing H2AK119ub1. We find that JARID2 and AEBP2 each interact with one of the two ubiquitin molecules in the nucleosome. A ubiquitin-interaction motif (UIM) in JARID2 is sandwiched between ubiquitin and the histone H2A-H2B acidic patch. Simultaneously, the tandem zinc-fingers of AEBP2 interact with the second ubiquitin and the histone H2A-H2B surface on the opposite side of the nucleosome. JARID2 plays a dual role in the H2AK119ub1 dependent stimulation of PRC2 through interactions with both EED via its K116 trimethylation and with the H2AK119-ubiquitin. AEBP2, on the other hand, appears to primarily serve as a scaffold contributing to the interaction between PRC2 and the H2AK119ub1 nucleosome. Our structure also provides a detailed visualization of the EZH2-nucleosome interface, revealing a segment of EZH2 (named “bridge helix”) that is stabilized as it bridges the EZH2(SET) domain, the H3 tail and the nucleosomal DNA. In addition to the role played by AEBP2 and JARID2 in PRC2 regulation by H2AK119ub1 recognition, we also observe that the presence of these cofactors partially overcomes the inhibitory effect that H3K4- and H3K36-trimethylation have on core PRC2. Together, our results reveal the central role played by cofactors JARID2 and AEBP2 in orchestrating the crosstalk between histone post-translational modifications and PRC2 methyltransferase activity.

Structural insights into the interactions of Polycomb Repressive Complex 2 with chromatin

2021 ◽  
Author(s):  
Akhil Gargey Iragavarapu ◽  
Liqi Yao ◽  
Vignesh Kasinath
Keyword(s):  
Target Genes ◽  
Histone H3 ◽  
Cell Type ◽  
Methyltransferase Activity ◽  
Post Translational Modifications ◽  
Polycomb Repressive Complex 2 ◽  
Polycomb Proteins ◽  
Polycomb Repressive Complexes ◽  
Structural Insights ◽  
Stimulation Of

Polycomb repressive complexes are a family of chromatin modifier enzymes which are critical for regulating gene expression and maintaining cell-type identity. The reversible chemical modifications of histone H3 and H2A by the Polycomb proteins are central to its ability to function as a gene silencer. PRC2 is both a reader and writer of the tri-methylation of histone H3 lysine 27 (H3K27me3) which serves as a marker for transcription repression, and heterochromatin boundaries. Over the last few years, several studies have provided key insights into the mechanisms regulating the recruitment and activation of PRC2 at Polycomb target genes. In this review, we highlight the recent structural studies which have elucidated the roles played by Polycomb cofactor proteins in mediating crosstalk between histone post-translational modifications and the recruitment of PRC2 and the stimulation of PRC2 methyltransferase activity.

scholarly journals JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications

Science ◽  
2021 ◽  
Vol 371 (6527) ◽  
pp. eabc3393
Author(s):  
Vignesh Kasinath ◽  
Curtis Beck ◽  
Paul Sauer ◽  
Simon Poepsel ◽  
Jennifer Kosmatka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Electron Microscopy ◽  
Histone Modifications ◽  
Gene Expression Regulation ◽  
Inhibitory Effect ◽  
Set Domain ◽  
Cryo Electron Microscopy ◽  
Nucleosomal Dna ◽  
Polycomb Protein ◽  
Polycomb Repressive Complexes

Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) cooperate to determine cell identity by epigenetic gene expression regulation. However, the mechanism of PRC2 recruitment by means of recognition of PRC1-mediated H2AK119ub1 remains poorly understood. Our PRC2 cryo–electron microscopy structure with cofactors JARID2 and AEBP2 bound to a H2AK119ub1-containing nucleosome reveals a bridge helix in EZH2 that connects the SET domain, H3 tail, and nucleosomal DNA. JARID2 and AEBP2 each interact with one ubiquitin and the H2A-H2B surface. JARID2 stimulates PRC2 through interactions with both the polycomb protein EED and the H2AK119-ubiquitin, whereas AEBP2 has an additional scaffolding role. The presence of these cofactors partially overcomes the inhibitory effect that H3K4me3 and H3K36me3 exert on core PRC2 (in the absence of cofactors). Our results support a key role for JARID2 and AEBP2 in the cross-talk between histone modifications and PRC2 activity.

scholarly journals Molecular basis of the selective methylation of histone H3.1

2014 ◽  
Vol 70 (a1) ◽  
pp. C1584-C1584 ◽  
Author(s):  
Jean-Francois Couture
Keyword(s):  
Structural Studies ◽  
Histone H4 ◽  
Set Domain ◽  
Methyltransferase Activity ◽  
Histone Proteins ◽  
Post Translational Modifications ◽  
Heterochromatin Formation ◽  
Functional Consequences ◽  
Binding Cleft ◽  
Critical Components

Histone proteins are critical components of the chromatin fiber. With the exception of histone H4, histone proteins exist as different variants with assigned specialized functions and are proposed to act as key elements for the selective deposition of histone post-translational modifications (PTMs). Among these variants, H3.3, which differs from H3.1 by only 5 residues, has been predominantly found in the proximity of genes that are highly expressed; however the functional consequences of that marking have remained enigmatic. Herein we report the crystal structure of the trithorax-related SET domain histone H3.1 K27 methyltransferase ATXR5 in complex with histone H3.1 and the product cofactor S-adenosylhomocysteine. Overall, the SET domain folds as an all β-strands structure preceded by the pre-SET domain which folds as three long α-helices. The histone H3 is maintained in an elongated conformation by residues located both in the SET and pre-SET domains of ATXR5. Interestingly, we found that a three residue loop folds back on top of the ATXR histone H3.1 binding cleft shielding the peptide from the solvent and maintaining P30 and A31 of H3.1 in a shallow hydrophobic pocket. Strikingly, substitution of A31 for a threonine, the corresponding residue in histone H3.3 in plant, severely impairs ATXR5 methyltransferase activity. Finally, biochemical and structural studies revealed that, with the exception of R26 mono-methylation, post-transcriptional modifications of residues neighboring K27 is detrimental to ATXR5 activity. Overall, our results suggest that the deposition of H3.3 serves to prevent K27 mono-methylation and heterochromatin formation during DNA replication.

scholarly journals Stimulation of adipocyte phospholipid methyltransferase activity by phorbol 12-myristate 13-acetate. Differential regulation of phospholipid methyltransferase and lipolysis

1987 ◽  
Vol 241 (3) ◽  
pp. 917-921 ◽  
Author(s):  
K L Kelly
Keyword(s):  
Phorbol Esters ◽  
Inhibitory Effect ◽  
Differential Regulation ◽  
Hormone Sensitive Lipase ◽  
Regulatory Pathway ◽  
Methyltransferase Activity ◽  
Hormone Sensitive ◽  
Intracellular Target ◽  
Dose Dependent ◽  
Stimulation Of

The present studies demonstrate that treatment of rat adipocytes with the phorbol ester phorbol 12-myristate 13-acetate (PMA) causes a dose-dependent stimulation of phospholipid methyltransferase (PLMT) activity. The stimulatory effect of PMA was not additive with that of isoprenaline or forskolin. The sensitivity of stimulated PLMT activity to inhibition by insulin, however, was decreased in the presence of PMA. The inhibitory effect of a maximal concentration of insulin on PLMT was unchanged in the presence of PMA. In contrast with the effects on PLMT, the lipolytic response of adipocytes to isoprenaline and the anti-lipolytic response to insulin were unaffected by PMA. These data suggest that PLMT is, whereas hormone-sensitive lipase is not, an intracellular target for the action of PMA. The lack of effect of PMA on lipolysis suggests that PLMT and hormone-sensitive lipase can be regulated by separate mechanisms. Furthermore, phorbol esters do not interfere in the regulatory pathway whereby insulin inhibits PMLT or lipolysis.

The Proteins Interacting with Prmt5 in Medaka (Oryzias latipes) Identified by Yeast Two-Hybridization

2020 ◽  
Vol 27 (10) ◽  
pp. 971-978
Author(s):  
Hao Shen ◽  
Xiaosha Zhang ◽  
Md. Abdullah Al Hafiz ◽  
Xiaoting Liang ◽  
Qiting Yao ◽  
...  
Keyword(s):  
Nadh Dehydrogenase ◽  
Binding Proteins ◽  
Zinc Fingers ◽  
Regulation Of Gene Expression ◽  
Apolipoprotein A ◽  
Cell Growth And Differentiation ◽  
Pr Domain ◽  
Partner Proteins ◽  
Apo Ai ◽  
Model Fish

Background: Prmt5 plays major role in regulation of gene expression, RNA processing, cell growth and differentiation, signal transduction, germ cell development, etc., in mammals. Prmt5 is also related to cancer. Knowing the proteins interacting with Prmt5 is important to understand Prmt5’s function in cells. Although there have been reports on proteins binding with Prmt5 in mammals, the partner proteins of Prmt5 in fish are still unclear. Objectives: The objective was to obtain proteins that bind with Prmt5 in medaka, a model fish. Methods: Yeast two hybridization was adopted to achieve the objective. Medaka Prmt5 was used as a bait to fish the prey, binding proteins in a cDNA library of medaka. Co-immunoprecipitation and in silicon analysis were performed to study the interaction of medaka Mep50 and Prmt5. Results: Eight proteins were identified to bind with Prmt5 from 69 preliminary positive colonies. The binding proteins are methylosome protein 50 (Mep50), apolipoprotein A-I-like (Apo-AI), PR domain containing protein 1a with zinc fingers (Prdm1a), Prdm1b, T-cell immunoglobulin mucin family member 3 (Tim-3), phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase (Paics), NADH dehydrogenase subunit 4 (ND4) and sciellin (Scl). Co-immunoprecipitation confirmed the interaction of medaka Prmt5 and Mep50. Predicted structures of medaka Prtm5 and Mep50 are similar to that of human PRMT5 and MEP50. Conclusion: Medaka Mep50, Prdm1a, Prdm1b, Apo-AI, Tim-3, Paics, ND4, and Scl bind with Prmt5.

PKC-independent inhibition of cardiac L-type Ca2+ channel current by phorbol esters

1996 ◽  
Vol 270 (2) ◽  
pp. H620-H627 ◽  
Author(s):  
T. Asai ◽  
L. M. Shuba ◽  
D. J. Pelzer ◽  
T. F. McDonald
Keyword(s):  
Protein Kinase C ◽  
Phorbol Esters ◽  
Ventricular Myocytes ◽  
Inhibitory Effect ◽  
Independent Action ◽  
Independent Manner ◽  
Channel Current ◽  
Kinase C ◽  
Channel Currents ◽  
Stimulation Of

Active and inactive phorbol esters were applied to guinea pig ventricular myocytes to study the responses of L-type Ca2+ (ICa,L) and L-type Na+ (INa,L) currents. Phorbol 12-myristate 13-acetate (PMA) (10-100 rM) never stimulated ICa,L or INa,L and frequently depressed them by 5-30% in a voltage-independent manner. However, the phorbol ester consistently activated delayed-rectifying K+ (IK) and Cl- currents. The inhibition of ICa,L occurred approximately 3 times faster than comonitored stimulation of IK, and ICa,L and INa,L were unaffected by two interventions that suppressed IK stimulation [pretreatment with 50 microM 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) and dialysis with pCa 11 versus standard pCa 9 solution]. Inactive phorbol esters 4 alpha-phorbol 12,13-didecanoate (alpha-PDD) and 4 alpha-phorbol had little effect on IK, but alpha-PDD had a PMA-like inhibitory effect on Ca2+ channel currents. We conclude that, unlike the stimulation of IK by PMA, inhibition of Ca2+ channel current by phorbol esters is a protein kinase C-independent action.

scholarly journals Histone transfer among chaperones

2012 ◽  
Vol 40 (2) ◽  
pp. 357-363 ◽  
Author(s):  
Wallace H. Liu ◽  
Mair E.A. Churchill
Keyword(s):  
Histone H3 ◽  
Histone Chaperone ◽  
Chromatin Assembly ◽  
Histone Chaperones ◽  
Nucleosome Assembly ◽  
Post Translational Modifications ◽  
Chromatin Dynamics ◽  
Nucleosomal Dna ◽  
Chaperone Interactions ◽  
Dependent Processes

The eukaryotic processes of nucleosome assembly and disassembly govern chromatin dynamics, in which histones exchange in a highly regulated manner to promote genome accessibility for all DNA-dependent processes. This regulation is partly carried out by histone chaperones, which serve multifaceted roles in co-ordinating the interactions of histone proteins with modification enzymes, nucleosome remodellers, other histone chaperones and nucleosomal DNA. The molecular details of the processes by which histone chaperones promote delivery of histones among their many functional partners are still largely undefined, but promise to offer insights into epigenome maintenance. In the present paper, we review recent findings on the histone chaperone interactions that guide the assembly of histones H3 and H4 into chromatin. This evidence supports the concepts of histone post-translational modifications and specific histone chaperone interactions as guiding principles for histone H3/H4 transactions during chromatin assembly.

Cross-talk along gastrointestinal tract during electrical stimulation: effects and mechanisms of gastric/colonic stimulation on rectal tone in dogs

2005 ◽  
Vol 288 (6) ◽  
pp. G1195-G1198 ◽  
Author(s):  
Shi Liu ◽  
Lijie Wang ◽  
J. D. Z. Chen
Keyword(s):  
Electrical Stimulation ◽  
Inhibitory Effect ◽  
Adrenergic Blockade ◽  
Rectal Compliance ◽  
Rectal Tone ◽  
Before And After ◽  
Sensory Functions ◽  
Sympathetic Pathway ◽  
Colonic Electrical Stimulation ◽  
Stimulation Of

Gastric electrical stimulation (GES) has been shown to alter motor and sensory functions of the stomach. However, its effects on other organs of the gut have rarely been investigated. The study was performed in 12 dogs implanted with two pairs of electrodes, one on the serosa of the stomach and the other on the colon. The study was composed of two experiments. Experiment 1 was designed to study the effects of GES on rectal tone and compliance in nine dogs compared with colonic electrical stimulation (CES). Rectal tone and compliance were assessed before and after GES or CES. Experiment 2 was performed to study the involvement of sympathetic pathway in 8 of the 12 dogs. The rectal tone was recorded for 30–40 min at baseline and 20 min after intravenous guanethidine. GES or CES was given for 20 min 20 min after the initiation of the infusion. It was found that both GES and CES reduced rectal tone with comparable potency. Rectal compliance was altered neither with GES, nor with CES. The inhibitory effect of GES but not CES on rectal tone was abolished by an adrenergic blockade, guanethidine. GES inhibited rectal tone with a comparable potency with CES but did not alter rectal compliance. The inhibitory effect of GES on rectal tone is mediated by the sympathetic pathway. It should be noted that electrical stimulation of one organ of the gut may have a beneficial or adverse effect on another organ of the gut.

Abstract 341: Synergistic Effects of Renal Dopamine and Gastrin Receptors in Hypertension

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Yue Chen ◽  
Shuo Zhen ◽  
Laureano Asico ◽  
Pedro Jose ◽  
Chunyu Zeng
Keyword(s):  
Atpase Activity ◽  
Sodium Excretion ◽  
Synergistic Effects ◽  
Inhibitory Effect ◽  
Receptor Interaction ◽  
Gastrin Receptor ◽  
Wky Rats ◽  
Link Type ◽  
Renal Dopamine ◽  
Stimulation Of

Oral NaCl produces stronger natriuresis and diuresis as compared with venous infusion of same amount of NaCl, indicating the existence of renal-gastric axis. Although numerous hormones are secreted in gastrointestinal tract, gastrin is evident one due to its natriuretic effects and taken-up by the renal proximal tubule (RPT) cells. We hypothesize that there is an interaction between gastrin and dopamine receptor in kidney, which synergistically increases sodium excretion, the impaired interaction would be involved in the pathogenesis of hypertension. In WKY rats, infusion of gastrin, via renal artery, induced natriuresis and diuresis, which was blocked in the presence of CI988, a gastrin receptor blocker. Similarly, the natriuretic and diuretic effect of fenoldopam, a D1-like receptor agonist, was blocked by the D1-like receptor antagonist, SCH23390 , indicating that gastrin and fenoldopam, via individual receptor, play natriuretic and diuretic effects. Our further study found that lower dosages of gastrin or fenoldopam could not induce natriuresis and diuresis alone, while putting together induced natriuretic and diuretic effects. The above-mentioned effects were lost in SHRs. We also found, in the presence of SCH23390 , gastrin-mediated natriuresis and diuresis was partially blocked. Similarly, in the presence of CI988, the natriuretic and diuretic effects of fenoldopam were partially blocked, indicating the interaction between gastrin and D1-like receptor. The gastrin/D1-like receptor interaction was also confirmed in the RPT cells. Stimulation of one receptor increased the expression of the other. Stimulation of either D1-like receptor or gastrin receptor inhibited the Na + -K + -ATPase activity in RPT cells, while in the presence of SCH23390 , the inhibitory effect of gastrin on Na + -K + -ATPase activity was partially blocked. In the presence of CI988, D1-like receptor-mediated inhibitory effect of Na + -K + -ATPase activity in RPT cells was partially inhibited. It indicated the synergistic effect between gastrin and D1-like receptor would increase the sodium excretion in WKY rats; the impaired interaction might be involved in the pathogenesis of hypertension.

scholarly journals An ontogenic study of receptor mechanisms by which acute administration of low-doses of methamphetamine suppresses DOI-induced 5-HT2A-receptor mediated head-twitch response in mice

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Yina Sun ◽  
Seetha Chebolu ◽  
Denise Henry ◽  
Sandeep Lankireddy ◽  
Nissar A. Darmani
Keyword(s):  
Suppressive Effect ◽  
Inhibitory Effect ◽  
Acute Administration ◽  
Low Doses ◽  
Head Twitch ◽  
Twitch Response ◽  
Way 100635 ◽  
Direct Acting ◽  
Head Twitch Response ◽  
Stimulation Of

Abstract Background Methamphetamine (MA) is a non-selective monoamine releaser and thus releases serotonin (5-HT), norepinephrine (NE) and dopamine (DA) from corresponding nerve terminals into synapses. DOI ((±)-2, 5-dimethoxy-4-iodoamphetamine) is a direct-acting serotonergic 5-HT2A/C receptor agonist and induces the head-twitch response (HTR) via stimulation of 5-HT2A receptor in mice. While more selective serotonin releasers such as d-fenfluramine evoke the HTR, monoamine reuptake blockers (e.g., cocaine) suppress the DOI-evoked HTR via indirect stimulation of serotonergic 5-HT1A- and adrenergic ɑ2-receptors. Since the induction of HTR by DOI is age-dependent, we investigated whether: (1) during development MA can evoke the HTR by itself, and (2) acute pretreatment with either the selective 5-HT2A receptor antagonist EMD 281014 or low-doses of MA can: (i) modulate the DOI-induced HTR in mice across postnatal days 20, 30 and 60, and (ii) alter the DOI-induced c-fos expression in mice prefrontal cortex (PFC). To further explore the possible modulatory effect of MA on DOI-induced HTR, we investigated whether blockade of inhibitory serotonergic 5-HT1A- or adrenergic ɑ2-receptors by corresponding selective antagonists (WAY 100635 or RS 79948, respectively), can prevent the effect of MA on DOI-induced HTR during aging. Results Although neither EMD 281014 nor MA by themselves could evoke the HTR, acute pretreatment with either EMD 281014 (0.01, 0.05 and 0.1 mg/kg, i.p.) or MA (1, 2.5, 5 mg/kg, i.p.), dose-dependently suppressed the DOI-induced HTR across ages. While WAY 100635 significantly reversed the inhibitory effect of MA in 20- and 30-day old mice, RS 79948 failed to significantly counter MA’s inhibitory effect. Moreover, DOI significantly increased c-fos expressions in several PFC regions. EMD 281014 prevented the DOI-induced increases in c-fos expression. Despite the inhibitory effect of MA on DOI-induced HTR, MA alone or in combination with DOI, significantly increased c-fos expression in several regions of the PFC. Conclusion The suppressive effect of MA on the DOI-evoked HTR appears to be mainly due to functional interactions between the HTR-inducing 5-HT2A receptor and the inhibitory 5-HT1A receptor. The MA-induced increase in c-fos expression in different PFC regions may be due to MA-evoked increases in synaptic concentrations of 5-HT, NE and/or DA.

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