Phase Separation of Chromatin Structure-related Biomolecules: A Driving Force for Epigenetic Regulations.

Intracellularly, membrane-less organelles are formed by spontaneous fusion and fission of macro-molecules in a process called phase separation, which plays an essential role in cellular activities. In certain disease states, such as cancers and neurodegenerative diseases, aberrant phase separations take place and participate in disease progression. Chromatin structure-related proteins, based on their characteristics and upon external stimuli, phase separate to exert functions like genome assembly, transcription regulation, and signal transduction. Moreover, many chromatin structure-related proteins, such as histones, histone-modifying enzymes, DNA-modifying enzymes, and DNA methylation binding proteins, are involved in epigenetic regulations through phase separation. This review introduces phase separation and how phase separation affects epigenetics with a focus on chromatin structure-related molecules.

A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury.

Acute kidney injury (AKI) exhibits high morbidity and mortality. Kidney injury molecule-1 (KIM1) is dramatically upregulated in renal tubules upon injury, and acts as a biomarker for various renal diseases. However, the exact role and underlying mechanism of KIM1 in the progression of AKI remain elusive. Herein, we report that renal tubular specific knockout of Kim1 attenuates cisplatin- or ischemia/reperfusion-induced AKI in male mice. Mechanistically, transcription factor Yin Yang 1 (YY1), which is downregulated upon AKI, binds to the promoter of KIM1 and represses its expression. Injury-induced KIM1 binds to the ECD domain of death receptor 5 (DR5), which activates DR5 and the following caspase cascade by promoting its multimerization, thus induces renal cell apoptosis and exacerbates AKI. Blocking the KIM1-DR5 interaction with rationally designed peptides exhibit reno-protective effects against AKI. Here, we reveal a YY1-KIM1-DR5 axis in the progression of AKI, which warrants future exploration as therapeutic targets.

Loss of renal tubular G9a benefits acute kidney injury by lowering focal lipid accumulation via CES1.

Surgery-induced renal ischemia and reperfusion (I/R) injury and nephrotoxic drugs like cisplatin can cause acute kidney injury (AKI), for which there is no effective therapy. Lipid accumulation is evident following AKI in renal tubules although the mechanisms and pathological effects are unclear. Here, we report that Ehmt2-encoded histone methyltransferase G9a is upregulated in patients and mouse kidneys after AKI. Renal tubular specific knockout of G9a (Ehmt2Ksp ) or pharmacological inhibition of G9a alleviates lipid accumulation associated with AKI. Mechanistically, G9a suppresses transcription of the lipolytic enzyme Ces1; moreover, G9a and farnesoid X receptor (FXR) competitively bind to the same promoter regions of Ces1. Ces1 is consistently observed to be downregulated in the kidney of AKI patients. Pharmacological inhibition of Ces1 increases lipid accumulation, exacerbates renal I/R-injury and eliminates the beneficial effects on AKI observed in Ehmt2Ksp mice. Furthermore, lipid-lowering atorvastatin and an FXR agonist alleviate AKI by activating Ces1 and reducing renal lipid accumulation. Together, our results reveal a G9a/FXR-Ces1 axis that affects the AKI outcome via regulating renal lipid accumulation.

Structural and Molecular Dynamics Analysis of Plant Serotonin N-Acetyltransferase Reveal an Acid/Base-Assisted Catalysis in Melatonin Biosynthesis.

Serotonin N-acetyltransferase (SNAT) is the key rate-limiting enzyme in melatonin biosynthesis. It mediates melatonin biosynthesis in plants by using serotonin and 5-methoxytryptamine (5-MT), but little is known of its underlying mechanisms. Herein, we present a detailed reaction mechanism of a SNAT from Oryza sativa through combined structural and molecular dynamics (MD) analysis. We report the crystal structures of plant SNAT in the apo and binary/ternary complex forms with acetyl-CoA (AcCoA), serotonin, and 5-MT. OsSNAT exhibits a unique enzymatically active dimeric fold not found in the known structures of arylalkylamine N-acetyltransferase (AANAT) family. The key residues W188, D189, D226, N220, and Y233 located around the active pocket are important in catalysis, confirmed by site-directed mutagenesis. Combined with MD simulations, we hypothesize a novel plausible catalytic mechanism in which D226 and Y233 function as catalytic base and acid during the acetyl-transfer reaction.

Method for Translation and Rotation Decoupling of Test Mass in Full-Maglev Vertical Superconducting Gravity Instruments.

For full-maglev vertical superconducting gravity instruments, displacement control in the non-sensitive axis is a key technique to suppress cross-coupling noise in a dynamic environment. Motion decoupling of the test mass is crucial for the control design. In practice, when levitated, the test mass is always in tilt, and unknown parameters will be introduced to the scale factors of displacement detection, which makes motion decoupling work extremely difficult. This paper proposes a method for decoupling the translation and rotation of the test mass in the non-sensitive axis for full-maglev vertical superconducting gravity instruments. In the method, superconducting circuits at low temperature and adjustable gain amplifiers at room temperature are combined to measure the difference between the scale factors caused by the tilt of the test mass. With the measured difference of the scale factors, the translation and rotation are decoupled according to the theoretical model. This method was verified with a test of a home-made full-maglev vertical superconducting accelerometer in which the translation and rotation were decoupled.

Effects of temperature fluctuations on a SQUID-based superconducting gravimeter.

A superconducting gravimeter based on the superconducting quantum interference device system is under development. As the main source of low-frequency noise, temperature fluctuations affect the resolution of superconducting gravimeters. In this study, a set of experimental devices was built to investigate the primary coupling processes of temperature fluctuations in superconducting gravimeters. Under the temperature modulation method, the effects of temperature fluctuations can be expressed as dΦ/dT = 342(2)Φ0/K, which, according to theoretical analysis, corresponds to a displacement change of (1.38 ± 0.04) × 10-7 m/K. Based on these results, the ambient temperature is controlled to within ±100 µK, and the equivalent effect of temperature fluctuations on our superconducting gravimeter is 0.5 µGal.

Crystal structure of Oryza sativa TDC reveals the substrate specificity for TDC-mediated melatonin biosynthesis.

Plant tryptophan decarboxylase (TDC) is a type II Pyridoxal-5'-phosphate-dependent decarboxylase (PLP_DC) that could be used as a target to genetically improve crops. However, lack of accurate structural information on plant TDC hampers the understanding of its decarboxylation mechanisms. In the present study, the crystal structures of Oryza sativa TDC (OsTDC) in its complexes with pyridoxal-5'-phosphate, tryptamine and serotonin were determined. The structures provide detailed interaction information between TDC and its substrates. The Y359 residue from the loop gate is a proton donor and forms a Lewis acid-base pair with serotonin/tryptamine, which is associated with product release. The H214 residue is responsible for PLP binding and proton transfer, and its proper interaction with Y359 is essential for OsTDC enzyme activity. The extra hydrogen bonds formed between the 5-hydroxyl group of serotonin and the backbone carboxyl groups of F104 and P105 explain the discrepancy between the catalytic activity of TDC in tryptophan and in 5-hydroxytryptophan. In addition, an evolutionary analysis revealed that type II PLP_DC originated from glutamic acid decarboxylase, potentially as an adaptive evolution of mechanism in organisms in extreme environments. This study is, to our knowledge, the first to present a detailed analysis of the crystal structure of OsTDC in these complexes. The information regarding the catalytic mechanism described here could facilitate the development of protocols to regulate melatonin levels and thereby contribute to crop improvement efforts to improve food security worldwide.

Tuning the Stiffness Balance Using Characteristic Frequencies as a Criterion for a Superconducting Gravity Gradiometer.

Tuning the stiffness balance is crucial to full-band common-mode rejection for a superconducting gravity gradiometer (SGG). A reliable method to do so has been proposed and experimentally tested. In the tuning scheme, the frequency response functions of the displacement of individual test mass upon common-mode accelerations were measured and thus determined a characteristic frequency for each test mass. A reduced difference in characteristic frequencies between the two test masses was utilized as the criterion for an effective tuning. Since the measurement of the characteristic frequencies does not depend on the scale factors of displacement detection, stiffness tuning can be done independently. We have tested this new method on a single-component SGG and obtained a reduction of two orders of magnitude in stiffness mismatch.