FXR/Menin-mediated epigenetic regulation of E2F3 expression controls ß-cell proliferation and is increased in islets from diabetic GK rats after RYGB.

Farnesoid X receptor (FXR) improves the function of islets, especially in the setting of Roux-en-Y gastric bypass (RYGB). Here we investigated how FXR activation regulates ß-cell proliferation and explored the potential link between FXR signaling and the menin pathway in controlling E2F3 expression, a key transcription factor for controlling adult ß-cell proliferation. Stimulation with the FXR agonist GW4064 or chenodeoxycholic acid (CDCA) increased E2F3 expression and ß-cell proliferation. Consistently, E2F3 knockdown abolished GW4064-induced proliferation. Treatment with GW4064 increased E2F3 expression in ß-cells via enhancing Steroid receptor coactivator-1 (SRC1) recruitment, increasing the pro-transcriptional acetylation of histone H3 at the E2f3 promoter. GW4064 treatment also decreased the association between FXR and menin, leading to the induction of FXR-mediated SRC1 recruitment. Mimicking the impact of FXR agonists, RYGB also increased E2F3 expression and ß-cell proliferation in GK rats and SD rats. These findings unravel the crucial role of the FXR/menin signaling in epigenetically controlling E2F3 expression and ß-cell proliferation, a mechanism possibly underlying RYGB-induced ß-cell proliferation.

Deep-Learning-Enabled High-Fidelity Absorbance Spectra from Distorted Dual-Comb Absorption Spectroscopy for Gas Quantification Analysis.

Dual-comb absorption spectroscopy has been a promising technique in laser spectroscopy due to its intrinsic advantages over broad spectral coverage, high resolution, high acquisition speed, and frequency accuracy. However, two primary challenges, including etalon effects and complex baseline extraction, still severely hinder its implementation in recovering absorbance spectra and subsequent quantification analysis. In this paper, we propose a deep learning enabled processing framework containing etalon removal and baseline extraction modules to obtain absorbance spectra from distorted dual-comb absorption spectroscopy. The etalon removal module utilizes a typical U-net model, and the baseline extraction module consists of a modified U-net model with physical constraint and an adaptive iteratively reweighted penalized least squares method serving as refinement. The training datasets combine experimental baselines and simulated gas absorption with different concentrations, fully exploiting prior information on gas absorption features from the HITRAN database. In the simulated and experimental test, the CO2 absorbance spectrum covering 25 cm-1 shows high consistency with the HITRAN database, of which the mean absolute error is less than 1% of the maximum absorbance value, and the retrieved concentration has a relative error under 2%, outperforming traditional approaches and indicating the potential practicality of our data processing framework. Hopefully, with a larger network volume and proper datasets, this processing framework can be extended to precise quantification analysis in more comprehensive applications such as atmospheric measurement and industrial monitoring.

GLP-1 signaling-regulated SNAP25 is involved in improved insulin secretion in diabetic GK rats after Roux-en-Y gastric bypass surgery.

BACKGROUND: Roux-en-Y gastric bypass surgery (RYGB) improves glucose-stimulated insulin secretion (GSIS) in type 2 diabetes (T2D) patients. SNAP25 plays an essential role in GSIS. Clinical studies indicate that enhanced GLP-1 signaling is an important contributor to the improved ß-cell function in T2D. We aimed to explore whether GLP-1-regulated SNAP25 is involved in the enhanced secretory function of ß-cells in diabetic Goto-Kakizaki (GK) rats after RYGB. METHODS AND RESULTS: RYGB or sham surgery was conducted in GK rats. mRNA and protein expression of SNAP25 was assessed by qPCR and Western blot, respectively. Occupancy of CREB and acetyltransferase CBP and acetylation of histone H3 (ACH3) at the Snap25 promoter were determined using ChIP assay. RYGB led to increased SNAP25 expression and CREB phosphorylation in islets from GK rats. Increased SNAP25 improved GSIS in ß-cells cultured in high glucose conditions. Consistent with increased plasma GLP-1 after RYGB, GLP-1R agonist exendin4 increased SNAP25 expression and CREB phosphorylation in ß-cells. Mechanistically, exendin4 promoted the recruitment of CREB and CBP, thereby increasing ACH3 at the Snap25 promoter. Consistently, inhibition of CBP attenuated the effect of exendin4 on SNAP25 expression. Furthermore, the knockdown of SNAP25 diminished the increase of GSIS potentiated by chronic GLP-1 culture in INS-1 832/13 cells. CONCLUSIONS: Our findings unravel the novel mechanisms of RYGB-enhanced SNAP25 expression in ß-cells, and SNAP25 may contribute to the improved ß-cell secretory function induced by RYGB.

Selective Cleavage of Methylene Linkage in Kraft Lignin over Commercial Zeolite in Isopropanol.

Lignin is an aromatic polymer that constitutes over 30 wt% of lignocellulosic biomass and is the most important source of renewable aromatics in nature. The global paper industry generates more than 70 million tons of Kraft lignin annually. Depolymerization of Kraft lignin to value-added monomers can significantly enhance the profitability of biorefinery. However, the method is impeded by the severe condensation of Kraft lignin during the pulping process, which forms robust C-C bonds and results in low monomer yields. In this study, we present a stepwise approach for producing valuable aromatic monomers from Kraft lignin through the cleavage of both C-O and C-C bonds. The approach initiated with complete cleavage of C-O bonds between lignin units within Kraft lignin through alcoholysis in isopropanol, resulting in a monomer yield of 8.9 %. Subsequently, the selective cleavage of methylene linkages present in the residual dimers and oligomers was achieved with commercial MCM-41 zeolite in the same pot, proceeding with an additional monomer yield of 4.0 %, thereby increasing the total monomer yield by 45 %. This work provides an avenue for increasing the depolymerization efficiency of Kraft lignin.

FXR controls insulin content by regulating Foxa2-mediated insulin transcription.

Farnesoid X receptor (FXR) is a nuclear ligand-activated receptor of bile acids that plays a role in the modulation of insulin content. However, the underlying molecular mechanisms remain unclear. Forkhead box a2 (Foxa2) is an important nuclear transcription factor in pancreatic ß-cells and is involved in ß-cell function. We aimed to explore the signaling mechanism downstream of FXR to regulate insulin content and underscore its association with Foxa2 and insulin gene (Ins) transcription. All experiments were conducted on FXR transgenic mice, INS-1 823/13 cells, and diabetic Goto-Kakizaki (GK) rats undergoing sham or Roux-en-Y gastric bypass (RYGB) surgery. Islets from FXR knockout mice and INS-1823/13 cells with FXR knockdown exhibited substantially lower insulin levels than that of controls. This was accompanied by decreased Foxa2 expression and Ins transcription. Conversely, FXR overexpression increased insulin content, concomitant with enhanced Foxa2 expression and Ins transcription in INS-1 823/13 cells. Moreover, FXR knockdown reduced FXR recruitment and H3K27 trimethylation in the Foxa2 promoter. Importantly, Foxa2 overexpression abrogated the adverse effects of FXR knockdown on Ins transcription and insulin content in INS-1 823/13 cells. Notably, RYGB surgery led to improved insulin content in diabetic GK rats, which was accompanied by upregulated FXR and Foxa2 expression and Ins transcription. Collectively, these data suggest that Foxa2 serves as the target gene of FXR in ß-cells and mediates FXR-enhanced Ins transcription. Additionally, the upregulated FXR/Foxa2 signaling cascade could contribute to the enhanced insulin content in diabetic GK rats after RYGB.

Tandem strategy of photocatalytic preoxidation-ultrasonic cavitation depolymerization for lignin valorization.

Tandem strategy for lignin utilization with photocatalytic preoxidation and ultrasonic cavitation depolymerization was proposed. Cornstalk residual lignin from industrial bioethanol process was first photocatalytically preoxidized under visible light by g-C3N4 and WO3/g-C3N4/h-BN (WCB) photocatalysts respectively, then obtained lignin samples were characterized to confirm the preoxidation with raw lignin as a blank. During photocatalytic preoxidation, benzyl hydroxyls in lignin was transformed to carbonyls, but a certain degree of lignin degradation and condensation was observed. In comparison, WCB-catalyzed photopreoxidation was more effective. Thereafter, lignin depolymerization was achieved by ultrasonic cavitation-assisted ethanololysis under optimal conditions. Compared with the mere ultrasonic cavitation depolymerization of pristine lignin, WCB-induced photocatalytic preoxidation improved the conversion rate by 14%, the light-oil yield by 26%, and the phenolic monomer yield by 35%. In general, the reported tandem method worked very well for the enhancement of lignin depolymerization and provided a new idea for the development of lignin valorization.

Radical footprinting and regularity revealing during the pyrolysis of technical lignins.

Revealing radical-mediated reactions is conducive to illustrate lignin pyrolysis and achieve subsequent regulation. Three technical lignins (hot-water-extracted lignin, kraft lignin, and soda lignin) were selected in this study and pyrolyzed from 400 °C to 700 °C, and their pyrolysis radicals in both chars and bio-oils were monitored with the electron paramagnetic resonance spectrometer. Results showed that spin concentrations of char radicals had a volcanic trend against the pyrolysis temperature, and reached the maximum values at 550-600 °C. However, the contents of bio-oil radicals were low during pyrolysis at low and medium temperature, but their spin concentrations exploded abruptly over 600-650 °C. Meanwhile, the bio-oil yields were found to drop after 550-600 °C, and the three inflection temperatures for char radicals, bio-oil radicals, and bio-oil yields were perfectly matched. These findings systematically elucidated the radical regularity in technical lignin pyrolysis and fundamentally contributed to the development of radical-mediated lignin pyrolysis mechanisms.

[Temporal Evolution and Source Appointment of Black Carbon Aerosol in Ordos During Summer and Autumn 2019].

In this study, black carbon (BC) aerosols were continuously observed using a seven-channel aethalometer (AE-33) in Ordos from August 12 to October 4, 2019; using this data combined with article matter (PM), pollutant gas, and meteorological element data; a HYSPLIT model; and potential source contribution function (PSCF) and concentration-weighted trajectory (CWT) models, we analyzed the temporal evolution and potential source appointment and main influence areas of BC. The results showed that the average of ρ(BC) was 882 ng·m-3, accounting for 6.08% of PM2.5. The ρ(BC) was mainly concentrated at 200-1000 ng·m-3, accounting for 55.9% of the total samples. In different BC mass concentration ranges, BCliquid was the mainstay, with an average proportion of 86%. The diurnal variations in BC and PM2.5 showed unimodal distributions, with peaks at 08:00 and 10:00, respectively, and peak concentrations increased by 24.3% and 47.2%, respectively. The diurnal variation in BCsolid showed a bimodal distribution, with peaks at 08:00 and 20:00, respectively. The diurnal variation in the BCliquid showed a unimodal distribution with a peak at 08:00. The strong correlation between BC and NO2 indicated a greater impact of vehicle emissions on BC concentration, whereas the weak correlation between BC and SO2 indicated a lower impact of industrial emissions on BC concentration. The dominant air masses affecting the Ordos could be divided into four categories. The southern air masses (35.6%) had the highest mass concentration of atmospheric pollutants, followed by the local air masses (26.9%) and the northwest air masses (18.8%), and the northeast air masses (18.7%) had the lowest mass concentration of pollutants. The influence of the Ordos on the downstream areas was mainly divided into the northeast air masses (40.9%), the northwest air masses (30.4%), and the southeast air masses (28.7%). High CWT value areas of BC were mainly located in the southern Yan'an-Tongchuan-Baoji-Hanzhong areas and Lvliang-Linfen-Sanmenxia-Nanyang areas. They were two long and narrow transmission belts with a weight mass concentration exceeding 1400 ng·m-3. High CWT value areas of BC had the greatest impact on the Wuhai-Bayannaoer-Baotou-Hohhot regions, with a weight concentration exceeding 900 ng·m-3. The long-range transportation of BC could reach the Yulin-Yan'an-Tongchuan-Baoji areas in the south, the Shuozhou-Datong-Beijing areas in the east, and the Xilin Gol League-Xing'an League-Hulunbuir areas in the northeast.

Lignin-first biorefinery of corn stalk via zirconium(IV) chloride/sodium hydroxide-catalyzed aerobic oxidation to produce phenolic carbonyls.

Lignin-first biorefinery of corn stalk via ZrCl4/NaOH-catalyzed aerobic oxidation for phenolic carbonyls production was reported. Under the co-catalysis of ZrCl4 and NaOH, lignin in corn stalk was oxidized into phenolic aldehydes (p-hydroxybenzaldehyde, vanillin, and syringaldehyde), ketones (p-hydroxyacetophenone, acetovanillone, and acetosyringone), acids (p-hydroxybenzoic acid and vanillic acid), and other derivatives. Reaction conditions, including time, temperature, ZrCl4 dosage, NaOH dosage, MeCN/H2O ratio, and initial O2 pressure were comprehensively screened, and the optimal lignin-derived monomer yields of 13.2 wt% was obtained. Among these aromatic compounds, phenolic aldehydes were the main products, and the overall selectivity of phenolic carbonyls was as high as 93%. Cellulose-rich residues after lignin-first oxidation were further characterized by thermogravimetry and analytical pyrolysis with corn stalk as the control, proving the good fragmentation and dissolution of lignin streams. In general, ZrCl4/NaOH-catalyzed lignin-first oxidation provided a novel approach for lignin valorization, and achieved the highest reported phenolic carbonyls selectivity.

Elucidating radical-mediated pyrolysis behaviors of preoxidized lignins.

Effect of lignin preoxidation on subsequent radical-mediated pyrolysis was discussed in this study. Technical hot-water-extracted lignin was preoxidized by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in diverse degrees and pyrolyzed under different temperatures. Characterizations indicated that preoxidation increased lignin oxygen contents and converted α-hydroxyls to α-carbonyls. These structural modifications caused by preoxidation reduced the thermal stability and pyrolysis reactivity of lignin, shifting lignin thermal decomposition to the low temperature region and inhibiting lignin pyrolysis into bio-oil fractions. However, recognition of species and yields of specific compounds via analytical pyrolysis declared that although preoxidation reduced product yields, it did not alter the reaction pathways. The fixed bed experiments proved the above findings and gave the gas compositions, mainly CO2 derived through decarbonylation. Both radicals in chars and bio-oils were monitored, and char radical concentrations were proportional to the preoxidation degrees. This work sorted out the performances of lignin pyrolysis after preoxidation and determined their negative effects.

Unmasking radical-mediated lignin pyrolysis after benzyl hydroxyl shielding.

Whether lignin benzyl hydroxyl shielding could promote its pyrolysis to phenolic compounds was investigated in this paper. Lignin benzyl hydroxyl was first preoxidized by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and stabilized by propionaldehyde respectively, then pyrolysis was conducted with milled wood lignin as a control. Organic stable radicals in pyrolytic chars were further detected to reveal lignin pyrolysis chemistry. Results showed that benzyl hydroxyl shielding process weakened lignin thermal stability, and decreased liquid yields regardless of the frequency of lignin ß-O-4 linkages. In addition, char yield grew after benzyl hydroxyl shielding. Radical concentration was inversely proportional to ß-O-4 content which indicated the non-negligible impact of shielded benzyl hydroxyl on lignin pyrolysis. Furthermore, gases from propionaldehyde stabilized lignin quenched its radicals. This work confirmed that lignin ß-O-4 linkages and shielded benzyl hydroxyl both played the great role in radical-mediated pyrolysis, but the enhancement of liquid products could not be achieved via benzyl hydroxyl shielding.

Could preoxidation always promote the subsequent hydroconversion of lignin? Two counterexamples catalyzed by Cu/CuMgAlOx in supercritical ethanol.

In this study, two counterexamples of lignin preoxidation-hydroconversion were reported. First, two lignin feedstocks were preoxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in acetonitrile with various dosages (15%, 30%, and 60%). Then, these preoxidized lignins (HELOs and MWLOs) were hydroconverted in supercritical ethanol catalyzed by Cu/CuMgAlOx. Total yields from HELOs were all higher than those from HEL, indicating the good promotion of DDQ preoxidation on the subsequent hydroconversion of HELOs, especially with the DDQ dosage of 15%. Differently, the promotion effect of DDQ preoxidation on the hydroconversion of MWLOs depended on the DDQ dosage as well as the reaction time. Through the comparison of two counterexamples, this work bursted the myth that preoxidation can always promote the subsequent hydroconversion of lignin, revealed the influence of lignin property, preoxidation degree, and reaction conditions on the subsequent hydroconversion of preoxidized lignin, and presented the new insight into the preoxidation-hydroconversion strategy for lignin.

ZIF-67 derived Co@NC/g-C3N4 as a photocatalyst for enhanced water splitting H2 evolution.

Graphitic carbon nitride (g-C3N4), as the one of the most promising photocatalysts, usually relies on noble metal co-catalysts in the photocatalytic water splitting H2 evolution process, which greatly increases the use cost. Here, a zeolite imidazole framework (ZIF-67) derived Co@NC/g-C3N4 composite was constructed through facile thermal condensation of ZIF-67 and melamine. The obtained Co@NC/g-C3N4 composites can drive water splitting H2 evolution without any noble metal co-catalyst under simulated sunlight. The optimal sample exhibits the highest H2 evolution rate of 161 µmol g-1·h-1, which is 6 times of pure g-C3N4. The N doped carbon in carbonized ZIF-67 can not only quickly capture separated electrons from g-C3N4, but also serve as the co-catalyst. The well dispersed cobalt intermediate on carbonized ZIF-67 also play a role in promoting electron conversion. The formation of junction between carbonized ZIF-67 and g-C3N4 could promote quick charge carrier separation and transfer. This work provides a new idea for photocatalytic H2 evolution without noble metal co-catalysis.

FXR-mediated epigenetic regulation of GLP-1R expression contributes to enhanced incretin effect in diabetes after RYGB.

In this study, we investigated how Roux-en-Y gastric bypass (RYGB) enhances glucagon-like peptide 1 (GLP-1) response in GK rats and explored the potential link between RYGB-stimulated BAs/FXR signalling and GLP-1R-linked signalling in ß-cells, a key pathway that regulates glucose-stimulated insulin secretion (GSIS). Here we show that RYGB restores GLP-1R expression in GK rat islets. This involves increased total BAs as well as chenodeoxycholic acid (CDCA), leading to FXR activation, increasing FXR binding to the promoter of Glp-1r and enhancing occupancy of histone acetyltransferase steroid receptor coactivator-1 (SRC1), thus increasing histone H3 acetylation at the promoter. These coordinated events bring about increased GLP-1R expression, resulting in greater GLP-1 response in ß-cells. Moreover, ablation of FXR suppressed the stimulatory effects of GLP-1. Thus, this study unravels the crucial role of the BAs/FXR/SRC1 axis-controlled GLP-1R expression in ß-cells, which results in enhanced incretin effect and normalized blood glucose of GK rats after RYGB.

In situ synthesis of a novel Mn3O4/g-C3N4 p-n heterostructure photocatalyst for water splitting.

Designing high-efficiency photocatalyst for photocatalytic water splitting is a considerable challenge. Herein, a new Mn3O4/g-C3N4 p-n heterostructure photocatalyst is prepared by an in-situ growth method. The introduction of Mn3O4 can enhance light absorption ability of g-C3N4. The Mn3O4/g-C3N4 photocatalyst exhibits outstanding photocatalytic activity for hydrogen evolution reaction (HER) efficiency of ~2700 µmol g-1h-1 at λ > 420 nm. For the separate reactions of H2 evolution and O2 evolution under simulated sunlight, the efficiencies of Mn3O4/g-C3N4 heterostructure photocatalyst are 3300 µmol g-1h-1 and 654 µmol g-1h-1, respectively. The p-n junction is also capable of catalyzing the overall water splitting reaction to generate H2 and O2 products in a stoichiometric molar ratio of 2:1. The formation of electric field in p-n Mn3O4/g-C3N4 junction promotes electron transfer and improves photocatalytic performance.

[Factors Influencing New Atmospheric Particle Formation in Ordos During Summer and Autumn 2019].

In this study, the aerosol number size distribution in the range of 10 nm-10 µm was collected from August 16 to October 04, 2019 at Ordos using a wide-range particle spectrometer (WPS). Combined with PM (PM2.5 and PM10), pollution gases, meteorological data, and the HYSPLIT model, the characteristics and impact factors of new particle formation (NPF) were discussed. The results indicated that there were 19 NPF events during the observation period, which have different effects on diurnal variation in aerosol number concentration in different modes. The NPF events caused a sharp increase in the number concentration of nucleation and Aitken mode aerosols, but had little effect on the number concentration of accumulation and coarse mode aerosols. The temperature, wind speed, and total solar radiation during NPF days were usually higher than those in non-NPF days, and the RH during NPF days was lower. On NPF days, the mass concentrations of PM2.5, PM10, CO, and NO2 were lower than those on non-NPF days, while the mass concentrations of O3 and SO2 were higher. NPF events were observed in 40.0% of northern air masses and 29.6% of southern air masses. There were significant differences in meteorological elements in different NPF event air mass types. The southern NPF event air mass type had the lowest wind speed and the highest RH, with averages of (2.4±1.5) m·s-1 and (48.8±10.8)%, respectively. The northern NPF event air mass type had the highest wind speed and total solar radiation, with averages of (4.2±1.9) m·s-1 and (664.5±255.6) W·m-2, respectively. The western air mass type of NPF event had the lowest RH, with an average of (29.8±12.7)%. The formation rates of new particles in the different air mass types of NPF events were similar, ranging from 1.5 to 1.8 cm-3·s-1. The largest growth rate was (12.7±13.6) nm·h-1 in the southern NPF event air mass type, which was 1.2 times and 1.4 times higher than the NPF events of northern air masses and western air masses.

Roux-en-Y gastric bypass enhances insulin secretion in type 2 diabetes via FXR-mediated TRPA1 expression.

OBJECTIVE: Roux-en-Y gastric bypass surgery (RYGB) improves the first phase of glucose-stimulated insulin secretion (GSIS) in patients with type 2 diabetes. How it does so remains unclear. Farnesoid X receptor (FXR), the nuclear receptor of bile acids (BAs), is implicated in bariatric surgery. Moreover, the transient receptor potential ankyrin 1 (TRPA1) channel is expressed in pancreatic ß-cells and involved in insulin secretion. We aimed to explore the role of BAs/FXR and TRPA1 in improved GSIS in diabetic rats after RYGB. METHODS: RYGB or sham surgery was conducted in spontaneous diabetic Goto-Kakizaki (GK) rats, or FXR or TRPA1 transgenic mice. Gene and protein expression of islets were assessed by qPCR and western blotting. Electrophysiological properties of single ß-cells were studied using patch-clamp technique. Binding of FXR and histone acetyltransferase steroid receptor coactivator-1 (SRC1) to the TRPA1 promoter, acetylated histone H3 (ACH3) levels at the TRPA1 promoter were determined using ChIP assays. GSIS was measured using enzyme-linked immunosorbent assays or intravenous glucose tolerance test (IVGTT). RESULTS: RYGB increases GSIS, particularly the first-phase of GSIS in both intact islets and GK rats in vivo, and ameliorates hyperglycemia of GK rats. Importantly, the effects of RYGB were attenuated in TRPA1-deficient mice. Moreover, GK ß-cells displayed significantly decreased TRPA1 expression and current. Patch-clamp recording revealed that TRPA1-/- ß-cells displayed a marked hyperpolarization and decreased glucose-evoked action potential firing, which was associated with impaired GSIS. RYGB restored TRPA1 expression and current in GK ß-cells. This was accompanied by improved glucose-evoked electrical activity and insulin secretion. Additionally, RYGB-induced TRPA1 expression involved BAs/FXR-mediated recruitment of SRC1, promoting ACH3 at the promoter of TRPA1. CONCLUSIONS: The BAs/FXR/SRC1 axis-mediated restoration of TRPA1 expression plays a critical role in the enhanced GSIS and remission of diabetes in GK rats after RYGB.

FXR Mediates Adenylyl Cyclase 8 Expression in Pancreatic ß-Cells.

Adenylyl cyclase 8 (ADCY8) and Farnesoid X Receptor (FXR) have been identified in pancreatic ß-cells and play important roles in insulin secretion. But the mechanisms underlying with respect to the regulation of ADCY8 expression in ß-cells, particularly whether FXR is involved, remain unexplored. We now show that ADCY8 expression is decreased in Goto-Kakizaki (GK) rat islets compared with healthy Wistar controls. We also found that reduced ADCY8 is associated with decreased expression of FXR. Consistently, ADCY8 expression was suppressed by the knockdown of FXR in INS-1 832/13 cells, as well as the islets from FXR knockout mice. On the contrary, ADCY8 expression was increased in FXR-overexpressed INS-1 832/13 cells or in the case of FXR activation. Mechanistically, FXR directly binds to Adcy8 promoter and recruits the histone acetyltransferase Steroid Receptor Coactivator 1 (SRC1), thereby resulting in the increased acetylation of histone H3 in Adcy8 locus, promoting Adcy8 gene transcription in ß-cells. Thus, this study indicates that FXR is a critical transcription factor that mediates ADCY8 expression in pancreatic ß-cells and has characterized the chromatin modification associated with Adcy8 transcription.

GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in ß cells.

Both menin and glucagon-like peptide 1 (GLP-1) pathways play central yet opposing role in regulating ß cell function, with menin suppressing, and GLP-1 promoting, ß cell function. However, little is known as to whether or how GLP-1 pathway represses menin function. Here, we show that GLP-1 signaling-activated protein kinase A (PKA) directly phosphorylates menin at the serine 487 residue, relieving menin-mediated suppression of insulin expression and cell proliferation. Mechanistically, Ser487-phosphorylated menin gains increased binding affinity to nuclear actin/myosin IIa proteins and gets sequestrated from the Ins1 promoter. This event leads to reduced binding of repressive epigenetic histone modifiers suppressor variegation 3-9 homologue protein 1 (SUV39H1) and histone deacetylases 1 (HDAC1) at the locus and subsequently increased Ins1 gene transcription. Ser487 phosphorylation of menin also increases expression of proproliferative cyclin D2 and ß cell proliferation. Our results have uncovered a previously unappreciated physiological link in which GLP-1 signaling suppresses menin function through phosphorylation-triggered and actin/myosin cytoskeletal protein-mediated derepression of gene transcription.