Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory effects. Here, an integrative pharmacological strategy was applied to identify the antiviral and anti-inflammatory bioactive compounds from Q-14. Overall, a total of 343 chemical compounds were initially characterized, and 60 prototype compounds in Q-14 were subsequently traced in plasma using ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. Among the 60 compounds, six compounds (magnolol, glycyrrhisoflavone, licoisoflavone A, emodin, echinatin, and quercetin) were identified showing a dose-dependent inhibition effect on the SARS-CoV-2 infection, including two inhibitors (echinatin and quercetin) of the main protease (Mpro), as well as two inhibitors (glycyrrhisoflavone and licoisoflavone A) of the RNA-dependent RNA polymerase (RdRp). Meanwhile, three anti-inflammatory components, including licochalcone B, echinatin, and glycyrrhisoflavone, were identified in a SARS-CoV-2-infected inflammatory cell model. In addition, glycyrrhisoflavone and licoisoflavone A also displayed strong inhibitory activities against cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4). Crystal structures of PDE4 in complex with glycyrrhisoflavone or licoisoflavone A were determined at resolutions of 1.54 Å and 1.65 Å, respectively, and both compounds bind in the active site of PDE4 with similar interactions. These findings will greatly stimulate the study of TCMT-NDRD against COVID-19.

Gibberellins regulate masculinization through the SpGAI-SpSTM module in dioecious spinach.

The sex of dioecious plants is mainly determined by genetic factors, but it can also be converted by environmental cues such as exogenous phytohormones. Gibberellic acids (GAs) are well-known inducers of flowering and sexual development, yet the pathway of gibberellin-induced sex conversion in dioecious spinach (Spinacia oleracea L.) remains elusive. Based on sex detection before and after GA3 application using T11A and SSR19 molecular markers, we confirmed and elevated the masculinization effect of GA on a single female plant through exogenous applications of GA3, showing complete conversion and functional stamens. Silencing of GIBBERELLIC ACID INSENSITIVE (SpGAI), a single DELLA family protein that is a central GA signaling repressor, results in similar masculinization. We also show that SpGAI can physically interact with the spinach KNOX transcription factor SHOOT MERISTEMLESS (SpSTM), which is a homolog of the flower meristem identity regulator STM in Arabidopsis. The silencing of SpSTM also masculinized female flowers in spinach. Furthermore, SpSTM could directly bind the intron of SpPI to repress SpPI expression in developing female flowers. Overall, our results suggest that GA induces a female masculinization process through the SpGAI-SpSTM-SpPI regulatory module in spinach. These insights may help to clarify the molecular mechanism underlying the sex conversion system in dioecious plants while also elucidating the physiological basis for the generation of unisexual flowers so as to establish dioecy in plants.

IFT54 directly interacts with kinesin-II and IFT dynein to regulate anterograde intraflagellar transport.

The intraflagellar transport (IFT) machinery consists of the anterograde motor kinesin-II, the retrograde motor IFT dynein, and the IFT-A and -B complexes. However, the interaction among IFT motors and IFT complexes during IFT remains elusive. Here, we show that the IFT-B protein IFT54 interacts with both kinesin-II and IFT dynein and regulates anterograde IFT. Deletion of residues 342-356 of Chlamydomonas IFT54 resulted in diminished anterograde traffic of IFT and accumulation of IFT motors and complexes in the proximal region of cilia. IFT54 directly interacted with kinesin-II and this interaction was strengthened for the IFT54Δ342-356 mutant in vitro and in vivo. The deletion of residues 261-275 of IFT54 reduced ciliary entry and anterograde traffic of IFT dynein with accumulation of IFT complexes near the ciliary tip. IFT54 directly interacted with IFT dynein subunit D1bLIC, and deletion of residues 261-275 reduced this interaction. The interactions between IFT54 and the IFT motors were also observed in mammalian cells. Our data indicate a central role for IFT54 in binding the IFT motors during anterograde IFT.

Rift Valley Fever Virus Nucleoprotein Triggers Autophagy to Dampen Antiviral Innate Immune Responses.

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes severe and potentially fatal hemorrhagic fever in humans. Autophagy is a self-degradative process that can restrict viral replication at multiple infection steps. In this study, we evaluated the effects of RVFV-triggered autophagy on viral replication and immune responses. Our results showed that RVFV infection triggered autophagosome formation and induced complete autophagy. Impairing autophagy flux by depleting autophagy-related gene 5 (ATG5), ATG7, or sequestosome 1 (SQSTM1) or treatment with autophagy inhibitors markedly reduced viral RNA synthesis and progeny virus production. Mechanistically, our findings demonstrated that the RVFV nucleoprotein (NP) C-terminal domain interacts with the autophagy receptor SQSTM1 and promotes the SQSTM1-microtubule-associated protein 1 light chain 3 B (LC3B) interaction and autophagy. Deletion of the NP C-terminal domain impaired the interaction between NP and SQSTM1 and its ability to trigger autophagy. Notably, RVFV-triggered autophagy promoted viral infection in macrophages but not in other tested cell types, including Huh7 hepatocytes and human umbilical vein endothelial cells, suggesting cell type specificity of this mechanism. It was further revealed that RVFV NP-triggered autophagy dampens antiviral innate immune responses in infected macrophages to promote viral replication. These results provide novel insights into the mechanisms of RVFV-triggered autophagy and indicate the potential of targeting the autophagy pathway to develop antivirals against RVFV. IMPORTANCE We showed that RVFV infection induced the complete autophagy process. Depletion of the core autophagy genes ATG5, ATG7, or SQSTM1 or pharmacologic inhibition of autophagy in macrophages strongly suppressed RVFV replication. We further revealed that the RVFV NP C-terminal domain interacted with SQSTM1 and enhanced the SQSTM1/LC3B interaction to promote autophagy. RVFV NP-triggered autophagy strongly inhibited virus-induced expression of interferon-stimulated genes in infected macrophages but not in other tested cell types. Our study provides novel insights into the mechanisms of RVFV-triggered autophagy and highlights the potential of targeting autophagy flux to develop antivirals against this virus.

Evolution of the spinach sex-linked region within a rarely recombining pericentromeric region.

Sex chromosomes have evolved independently in many different plant lineages. Here, we describe reference genomes for spinach (Spinacia oleracea) X and Y haplotypes by sequencing homozygous XX females and YY males. The long arm of 185-Mb chromosome 4 carries a 13-Mb X-linked region (XLR) and 24.1-Mb Y-linked region (YLR), of which 10 Mb is Y specific. We describe evidence that this reflects insertions of autosomal sequences creating a "Y duplication region" or "YDR" whose presence probably directly reduces genetic recombination in the immediately flanking regions, although both the X and Y sex-linked regions are within a large pericentromeric region of chromosome 4 that recombines rarely in meiosis of both sexes. Sequence divergence estimates using synonymous sites indicate that YDR genes started diverging from their likely autosomal progenitors about 3 MYA, around the time when the flanking YLR stopped recombining with the XLR. These flanking regions have a higher density of repetitive sequences in the YY than the XX assembly and include slightly more pseudogenes compared with the XLR, and the YLR has lost about 11% of the ancestral genes, suggesting some degeneration. Insertion of a male-determining factor would have caused Y linkage across the entire pericentromeric region, creating physically small, highly recombining, terminal pseudoautosomal regions. These findings provide a broader understanding of the origin of sex chromosomes in spinach.

The application of the ICD-10 for antepartum stillbirth patients in a referral centre of Eastern China: a retrospective study from 2015 to 2022.

BACKGROUND: The causes of some stillbirths are unclear, and additional work must be done to investigate the risk factors for stillbirths. OBJECTIVE: To apply the International Classification of Disease-10 (ICD-10) for antepartum stillbirth at a referral center in eastern China. METHODS: Antepartum stillbirths were grouped according to the cause of death according to the International Classification of Disease-10 (ICD-10) criteria. The main maternal condition at the time of antepartum stillbirth was assigned to each patient. RESULTS: Antepartum stillbirths were mostly classified as fetal deaths of unspecified cause, antepartum hypoxia. Although more than half of the mothers were without an identified condition at the time of the antepartum stillbirth, where there was a maternal condition associated with perinatal death, maternal medical and surgical conditions and maternal complications during pregnancy were most common. Of all the stillbirths, 51.2% occurred between 28 and 37 weeks of gestation, the main causes of stillbirth at different gestational ages also differed. Autopsy and chromosomal microarray analysis (CMA) were recommended in all stillbirths, but only 3.6% received autopsy and 10.5% underwent chromosomal microarray analysis. CONCLUSIONS: The ICD-10 is helpful in classifying the causes of stillbirths, but more than half of the stillbirths in our study were unexplained; therefore, additional work must be done. And the ICD-10 score may need to be improved, such as by classifying stillbirths according to gestational age. Autopsy and CMA could help determine the cause of stillbirth, but the acceptance of these methods is currently low.

Effect of cervical Bishop score on induction of labor at term in primiparas using Foley catheter balloon: a retrospective study.

BACKGROUND: Previous studies had found that the mechanical methods were as effective as pharmacological methods in achieving vaginal delivery. However, whether balloon catheter induction is suitable for women with severe cervical immaturity and whether it will increase the related risks still need to be further explored. RESEARCH AIM: To evaluate the efficacy and safety of Foley catheter balloon for labor induction at term in primiparas with different cervical scores. METHODS: A total of 688 primiparas who received cervical ripening with a Foley catheter balloon were recruited in this study. They were divided into 2 groups: Group 1 (Bishop score ≤ 3) and Group 2 (3 < Bishop score < 7). Detailed medical data before and after using of balloon were faithfully recorded. RESULTS: The cervical Bishop scores of the two groups after catheter placement were all significantly higher than those before (Group 1: 5.49 ± 1.31 VS 2.83 ± 0.39, P<0.05; Group 2: 6.09 ± 1.00 VS 4.45 ± 0.59, P<0.05). The success rate of labor induction in group 2 was higher than that in group 1 (P<0.05). The incidence of intrauterine infection in Group 1 was higher than that in Group 2 (18.3% VS 11.3%, P<0.05). CONCLUSION: The success rates of induction of labor by Foley catheter balloon were different in primiparas with different cervical conditions, the failure rate of induction of labor and the incidence of intrauterine infection were higher in primiparas with severe cervical immaturity.

Di-Isatropolone C, a Spontaneous Isatropolone C Dimer Derivative with Autophagy Activity.

Isatropolone C from Streptomyces sp. CPCC 204095 features a fused cyclopentadienone-tropolone-oxacyclohexadiene tricyclic moiety in its structure. Herein, we report an isatropolone C dimer derivative, di-isatropolone C, formed spontaneously from isatropolone C in methanol. Notably, the structure of di-isatropolone C resolved by NMR reveals a newly formed cyclopentane ring to associate the two isatropolone C monomers. The configurations of four chiral carbons, including a ketal one, in the cyclopentane ring are assigned using quantum NMR calculations and DP4+ probability. The plausible molecular mechanism for di-isatropolone C formation is proposed, in which complex dehydrogenative C-C bond coupling may have happened to connect the two isatropolone C monomers. Like isatropolone C, di-isatropolone C shows the biological activity of inducing autophagy in HepG2 cells.

Chromosome-level assembly of the Neolamarckia cadamba genome provides insights into the evolution of cadambine biosynthesis.

Neolamarckia cadamba (Roxb.), a close relative of Coffea canephora and Ophiorrhiza pumila, is an important traditional medicine in Southeast Asia. Three major glycosidic monoterpenoid indole alkaloids (MIAs), cadambine and its derivatives 3ß-isodihydrocadambine and 3ß-dihydrocadambine, accumulate in the bark and leaves, and exhibit antimalarial, antiproliferative, antioxidant, anticancer and anti-inflammatory activities. Here, we report a chromosome-scale N. cadamba genome, with 744.5 Mb assembled into 22 pseudochromosomes with contig N50 and scaffold N50 of 824.14 Kb and 29.20 Mb, respectively. Comparative genomic analysis of N. cadamba with Co. canephora revealed that N. cadamba underwent a relatively recent whole-genome duplication (WGD) event after diverging from Co. canephora, which contributed to the evolution of the MIA biosynthetic pathway. We determined the key intermediates of the cadambine biosynthetic pathway and further showed that NcSTR1 catalyzed the synthesis of strictosidine in N. cadamba. A new component, epoxystrictosidine (C27H34N2O10, m/z 547.2285), was identified in the cadambine biosynthetic pathway. Combining genome-wide association study (GWAS), population analysis, multi-omics analysis and metabolic gene cluster prediction, this study will shed light on the evolution of MIA biosynthetic pathway genes. This N. cadamba reference sequence will accelerate the understanding of the evolutionary history of specific metabolic pathways and facilitate the development of tools for enhancing bioactive productivity by metabolic engineering in microbes or by molecular breeding in plants.

Lineage-specific amplification and epigenetic regulation of LTR-retrotransposons contribute to the structure, evolution, and function of Fabaceae species.

BACKGROUND: Long terminal repeat (LTR)-retrotransposons (LTR-RTs) are ubiquitous and make up the majority of nearly all sequenced plant genomes, whereas their pivotal roles in genome evolution, gene expression regulation as well as their epigenetic regulation are still not well understood, especially in a large number of closely related species. RESULTS: Here, we analyzed the abundance and dynamic evolution of LTR-RTs in 54 species from an economically and agronomically important family, Fabaceae, and also selected two representative species for further analysis in expression of associated genes, transcriptional activity and DNA methylation patterns of LTR-RTs. Annotation results revealed highly varied proportions of LTR-RTs in these genomes (5.1%~68.4%) and their correlation with genome size was highly positive, and they were significantly contributed to the variance in genome size through species-specific unique amplifications. Almost all of the intact LTR-RTs were inserted into the genomes 4 Mya (million years ago), and more than 50% of them were inserted in the last 0.5 million years, suggesting that recent amplifications of LTR-RTs were an important force driving genome evolution. In addition, expression levels of genes with intronic, promoter, and downstream LTR-RT insertions of Glycine max and Vigna radiata, two agronomically important crops in Fabaceae, showed that the LTR-RTs located in promoter or downstream regions suppressed associated gene expression. However, the LTR-RTs within introns promoted gene expression or had no contribution to gene expression. Additionally, shorter and younger LTR-RTs maintained higher mobility and transpositional potential. Compared with the transcriptionally silent LTR-RTs, the active elements showed significantly lower DNA methylation levels in all three contexts. The distributions of transcriptionally active and silent LTR-RT methylation varied across different lineages due to the position of LTR-RTs located or potentially epigenetic regulation. CONCLUSION: Lineage-specific amplification patterns were observed and higher methylation level may repress the activity of LTR-RTs, further influence evolution in Fabaceae species. This study offers valuable clues into the evolution, function, transcriptional activity and epigenetic regulation of LTR-RTs in Fabaceae genomes.

Transition of allele-specific DNA hydroxymethylation at regulatory loci is associated with phenotypic variation in monozygotic twins discordant for psychiatric disorders.

BACKGROUND: Major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic mental illnesses. Their non-Mendelian features, such as those observed in monozygotic twins discordant for SCZ or BPD, are likely complicated by environmental modifiers of genetic effects. 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark in gene regulation, and whether it is linked to genetic variants that contribute to non-Mendelian features remains largely unexplored. METHODS: We combined the 5hmC-selective chemical labeling method (5hmC-seq) and whole-genome sequencing (WGS) analysis of peripheral blood DNA obtained from monozygotic (MZ) twins discordant for SCZ or BPD to identify allelic imbalances in hydroxymethylome maps, and examined association of allele-specific hydroxymethylation (AShM) transition with disease susceptibility based on Bayes factors (BF) derived from the Bayesian generalized additive linear mixed model. We then performed multi-omics integrative analysis to determine the molecular pathogenic basis of those AShM sites. We finally employed luciferase reporter, CRISPR/Cas9 technology, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), PCR, FM4-64 imaging analysis, and RNA sequencing to validate the function of interested AShM sites in the human neuroblastoma SK-N-SH cells and human embryonic kidney 293T (HEK293T) cells. RESULTS: We identified thousands of genetic variants associated with AShM imbalances that exhibited phenotypic variation-associated AShM changes at regulatory loci. These AShM marks showed plausible associations with SCZ or BPD based on their effects on interactions among transcription factors (TFs), DNA methylation levels, or other epigenomic marks and thus contributed to dysregulated gene expression, which ultimately increased disease susceptibility. We then validated that competitive binding of POU3F2 on the alternative allele at the AShM site rs4558409 (G/T) in PLLP-enhanced PLLP expression, while the hydroxymethylated alternative allele, which alleviated the POU3F2 binding activity at the rs4558409 site, might be associated with the downregulated PLLP expression observed in BPD or SCZ. Moreover, disruption of rs4558409 promoted neural development and vesicle trafficking. CONCLUSION: Our study provides a powerful strategy for prioritizing regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic factors in mediating SCZ or BPD susceptibility.

A rapid method for assembly of single chromosome and identification of sex determination region based on single-chromosome sequencing.

The sex-determining-region (SDR) may offer the best prospects for studying sex-determining gene, recombination suppression, and chromosome heteromorphism. However, current progress of SDR identification and cloning showed following shortcomings: large near-isogenic lines need to be constructed, and a relatively large population is needed; the cost of whole-genome sequencing and assembly is high. Herein, the X/Y chromosomes of Spinacia oleracea L. subsp. turkestanica were successfully microdissected and assembled using single-chromosome sequencing. The assembly length of X and Y chromosome is c. 192.1 and 195.2 Mb, respectively. Three large inversions existed between X and Y chromosome. The SDR size of X and Y chromosome is c. 13.2 and 24.1 Mb, respectively. MSY region and six male-biased genes were identified. A Y-chromosome-specific marker in SDR was constructed and used to verify the chromosome assembly quality at cytological level via fluorescence in situ hybridization. Meanwhile, it was observed that the SDR located on long arm of Y chromosome and near the centromere. Overall, a technical system was successfully established for rapid cloning the SDR and it is also applicable to rapid assembly of specific chromosome in other plants. Furthermore, this study laid a foundation for studying the molecular mechanism of sex chromosome evolution in spinach.

A PML/RARα direct target atlas redefines transcriptional deregulation in acute promyelocytic leukemia.

Transcriptional deregulation initiated by oncogenic fusion proteins plays a vital role in leukemia. The prevailing view is that the oncogenic fusion protein promyelocytic leukemia/retinoic acid receptor-α (PML/RARα), generated by the chromosome translocation t(15;17), functions as a transcriptional repressor in acute promyelocytic leukemia (APL). Here, we provide rich evidence of how PML/RARα drives oncogenesis through both repressive and activating functions, particularly the importance of the newly identified activation role for the leukemogenesis of APL. The activating function of PML/RARα is achieved by recruiting both abundant P300 and HDAC1 and by the formation of super-enhancers. All-trans retinoic acid and arsenic trioxide, 2 widely used drugs in APL therapy, exert synergistic effects on controlling super-enhancer-associated PML/RARα-regulated targets in APL cells. We use a series of in vitro and in vivo experiments to demonstrate that PML/RARα-activated target gene GFI1 is necessary for the maintenance of APL cells and that PML/RARα, likely oligomerized, transactivates GFI1 through chromatin conformation at the super-enhancer region. Finally, we profile GFI1 targets and reveal the interplay between GFI1 and PML/RARα on chromatin in coregulating target genes. Our study provides genomic insight into the dual role of fusion transcription factors in transcriptional deregulation to drive leukemia development, highlighting the importance of globally dissecting regulatory circuits.

Iterative Methylation Leads to 3-Methylchuangxinmycin Production in Actinoplanes tsinanensis CPCC 200056.

A new congener of chuangxinmycin (CM) was identified from Actinoplanes tsinanensis CPCC 200056. Its structure was determined as 3-methylchuangxinmycin (MCM) by 1D and 2D NMR. MCM could be generated in vivo from CM by heterologous expression of the vitamin B12-dependent radical SAM enzyme CxnA/A1 responsible for methylation of 3-demethylchuangxinmycin (DCM) in CM biosynthesis, indicating that CxnA/A1 could perform iterative methylation for MCM production. In vitro assays revealed significant activities of CM, DCM, and MCM against Mycobacterium tuberculosis H37Rv and clinically isolated isoniazid/rifampin-resistant M. tuberculosis, suggesting that CM and its derivatives may have potential for antituberculosis drug development.

FLS2 is a CDK-like kinase that directly binds IFT70 and is required for proper ciliary disassembly in Chlamydomonas.

Intraflagellar transport (IFT) is required for ciliary assembly and maintenance. While disruption of IFT may trigger ciliary disassembly, we show here that IFT mediated transport of a CDK-like kinase ensures proper ciliary disassembly. Mutations in flagellar shortening 2 (FLS2), encoding a CDK-like kinase, lead to retardation of cilia resorption and delay of cell cycle progression. Stimulation for ciliary disassembly induces gradual dephosphorylation of FLS2 accompanied with gradual inactivation. Loss of FLS2 or its kinase activity induces early onset of kinesin13 phosphorylation in cilia. FLS2 is predominantly localized in the cell body, however, it is transported to cilia upon induction of ciliary disassembly. FLS2 directly interacts with IFT70 and loss of this interaction inhibits its ciliary transport, leading to dysregulation of kinesin13 phosphorylation and retardation of ciliary disassembly. Thus, this work demonstrates that IFT plays active roles in controlling proper ciliary disassembly by transporting a protein kinase to cilia to regulate a microtubule depolymerizer.

DNA Methylation is Involved in Sex Determination in Spinach.

DNA methylation plays a critical role in the modulation of gene expression. The role of DNA methylation in sex determination was investigated in spinach. The differentiated cytosine CpG methylation profiles of CCGG motifs were assessed with methylation sensitivity amplification polymorphism (MSAP) in spinach. Among 442 DNA fragments from four plants, 134 methylated fragments were found. Relative proportions of methylation sites were 28.8% in male plants and 31.8% in female plants. At the same time, cytosine methylation levels were higher in females than in males in CCGG motifs of genomes in the spinach. These findings suggest that methylation of CG islands is involved in sex determination and differentiation in spinach.

Miconazole exerts disease-modifying effects during epilepsy by suppressing neuroinflammation via NF-κB pathway and iNOS production.

Neuroinflammation contributes to the generation of epilepsy and has been proposed as an effective therapeutic target. Recent studies have uncovered the potential effects of the anti-fungal drug miconazole for treating various brain diseases by suppressing neuroinflammation but have not yet been studied in epilepsy. Here, we investigated the effects of different doses of miconazole (5, 20, 80 mg/kg) on seizure threshold, inflammatory cytokines release, and glial cells activation in the pilocarpine (PILO) pentylenetetrazole (PTZ), and intrahippocampal kainic acid (IHKA) models. We demonstrated that 5 and 20 mg/kg miconazole increased seizure threshold, but only 20 mg/kg miconazole reduced inflammatory cytokines release, glial cells activation, and morphological alteration during the early post-induction period (24 h, 3 days). We further investigated the effects of 20 mg/kg miconazole on epilepsy (4 weeks after KA injection). We found that miconazole significantly attenuated cytokines production, glial cells activation, microglial morphological changes, frequency and duration of recurrent hippocampal paroxysmal discharges (HPDs), and neuronal and synaptic damage in the hippocampus during epilepsy. In addition, miconazole suppressed the KA-induced activation of the NF-κB pathway and iNOS production. Our results indicated miconazole to be an effective drug for disease-modifying effects during epilepsy, which may act by attenuating neuroinflammation through the suppression of NF-κB activation and iNOS production. At appropriate doses, miconazole may be a safe and effective approved drug that can easily be repositioned for clinical practice.

Interplay between hypertriglyceridemia and acute promyelocytic leukemia mediated by the cooperation of peroxisome proliferator-activated receptor-α with the PML/RAR α fusion protein on super-enhancers.

Patients with newly diagnosed acute promyelocytic leukemia (APL) are often obese or overweight, accompanied by metabolic disorders, such as dyslipidemia. However, the link between dyslipidemia and leukemia is obscure. Here, we conducted a retrospective study containing 1,412 cases (319 newly diagnosed APL patients, 393 newly diagnosed non-APL acute myeloid leukemia patients, and 700 non-tumor controls) and found that APL patients had higher triglyceride levels than non- APL and control groups. Using clinical data, we revealed that hypertriglyceridemia served as a risk factor for early death in APL patients, and there was a positive correlation between triglyceride levels and leukocyte counts. RNA sequencing analysis of APL patients having high or normal triglyceride levels highlighted the contribution of peroxisome proliferatoractivated receptor-α (PPARα), a crucial regulator of cell metabolism and a transcription factor involved in cancer development. The genome-wide chromatin occupancy of PPARα revealed that PPARα co-existed with PML/RARα within the super-enhancer regions to promote cell proliferation. PPARα knockdown affected the expression of target genes responsible for APL proliferation, including FLT3, and functionally inhibited the proliferation of APL cells. Moreover, in vivo results in mice having high fat diet-induced high triglyceride levels supported the connection between high triglyceride levels and the leukemic burden, as well as the involvement of PPARα-mediated-FLT3 activation in the proliferation of APL cells. Our findings shed light on the association between APL proliferation and high triglyceride levels and provide a genetic link to PPARα-mediated hyperlipidemia in APL.

LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia.

Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.

Allele-specific DNA methylation maps in monozygotic twins discordant for psychiatric disorders reveal that disease-associated switching at the EIPR1 regulatory loci modulates neural function.

The non-Mendelian features of phenotypic variations within monozygotic twins are likely complicated by environmental modifiers of genetic effects that have yet to be elucidated. Here, we performed methylome and genome analyses of blood DNA from psychiatric disorder-discordant monozygotic twins to study how allele-specific methylation (ASM) mediates phenotypic variations. We identified that thousands of genetic variants with ASM imbalances exhibit phenotypic variation-associated switching at regulatory loci. These ASMs have plausible causal associations with psychiatric disorders through effects on interactions between transcription factors, DNA methylations, and other epigenomic markers and then contribute to dysregulated gene expression, which eventually increases disease susceptibility. Moreover, we also experimentally validated the model that the rs4854158 alternative C allele at an ASM switching regulatory locus of EIPR1 encoding endosome-associated recycling protein-interacting protein 1, is associated with demethylation and higher RNA expression and shows lower TF binding affinities in unaffected controls. An epigenetic ASM switching induces C allele hypermethylation and then recruits repressive Polycomb repressive complex 2 (PRC2), reinforces trimethylation of lysine 27 on histone 3 and inhibits its transcriptional activity, thus leading to downregulation of EIPR1 in schizophrenia. Moreover, disruption of rs4854158 induces gain of EIPR1 function and promotes neural development and vesicle trafficking. Our study provides a powerful framework for identifying regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic variants in mediating psychiatric disorder susceptibility.