Allele-specific RNA N 6-methyladenosine modifications reveal functional genetic variants in human tissues.

An intricate network of cis- and trans-elements acts on RNA N 6-methyladenosine (m6A), which in turn may affect gene expression and, ultimately, human health. A complete understanding of this network requires new approaches to accurately measure the subtle m6A differences arising from genetic variants, many of which have been associated with common diseases. To address this gap, we developed a method to accurately and sensitively detect transcriptome-wide allele-specific m6A (ASm6A) from MeRIP-seq data and applied it to uncover 12,056 high-confidence ASm6A modifications from 25 human tissues. We also identified 1184 putative functional variants for ASm6A regulation, a subset of which we experimentally validated. Importantly, we found that many of these ASm6A-associated genetic variants were enriched for common disease-associated and complex trait-associated risk loci, and verified that two disease risk variants can change m6A modification status. Together, this work provides a tool to detangle the dynamic network of RNA modifications at the allelic level and highlights the interplay of m6A and genetics in human health and disease.

Prevention strategies for the recurrence of venous leg ulcers: A scoping review.

Venous leg ulcer (VLU) is the most severe manifestations of chronic venous disease, which has characterized by slow healing and high recurrence rates. This typically recalcitrant and recurring condition significantly impairs quality of life, prevention of VLU recurrence is essential for helping to reduce the huge burden of patients and health resources, the purpose of this scoping review is to analyse and determine the intervention measures for preventing recurrence of the current reported, to better inform healthcare professionals and patients. The PubMed, Embase, Web of Science, Cochrane Library databases, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wan Fang Data and Chongqing VIP Information (CQVIP) were accessed up to June 17, 2023. This scoping review followed the five-steps framework described by Arksey and O'Malley and the PRISMA extension was used to report the review. Eleven articles were included with a total of 1503 patients, and adopted the four effective measures: compression therapy, physical activity, health education, and self-care. To conclude, the use of high pressure compression treatment for life, supplementary exercise therapy, and strengthen health education to promote self-care are recommended strategies of VLU prevention and recurrence. In addition, the importance of multi-disciplinary teams to participate in the care of VLU in crucial.

Identification of circular RNAs as regulators and noninvasive biomarkers for placenta accreta spectrum.

In brief: Placenta accreta spectrum (PAS) has an urgent need for reliable prenatal biomarkers. This study profiled the circular RNAs (circRNAs) in PAS placenta and maternal blood and identified two circRNAs can regulate trophoblast cells invasion and serve as noninvasive prenatal biomarkers for PAS prediction. Abstract: PAS is one of the most alarming obstetric diseases with high mortality rates. The regulating mechanism underlying PAS remains to be investigated, and reliable blood biomarkers for PAS have not emerged. Circular RNAs (circRNAs) have become important regulators and biomarkers for disparate human diseases. However, the circRNA profiles of PAS were not reported, and the regulatory role and predictive value of circRNAs in PAS were unknown. Here, we comprehensively profiled the circRNAs in the placenta of PAS by transcriptome sequencing and analysis and uncovered 217 abnormally expressed circRNAs. Through competing endogenous RNA network analysis, we found that the target genes of upregulated circRNAs in PAS were enriched in placenta development-related pathways and further uncovered two circRNAs, circPHACTR4 and circZMYM4, that could regulate trophoblast cells invasion and migration in vitro. Finally, we verified that circPHACTR4 and circZMYM4 were also upregulated in the maternal peripheral blood of PAS women before delivery using transcriptome sequencing and RT-qPCR and evaluated their predictive value by ROC curves. We found that circPHACTR4 and circZMYM4 could serve as effective predicting biomarkers for PAS (area under the curve (AUC): 0.86 and 0.85) and propose an improved model for PAS prenatal prediction by combining the conventional ultrasound diagnosis with the new circRNA predictive factors (AUC: 0.91, specificity: 0.89, sensitivity: 0.82).Altogether, this work provides new resources for deciphering the biological roles of circRNAs in PAS, identified two circRNAs that could regulate trophoblast cells invasion during placentation, and revealed two noninvasive diagnostic markers for PAS.

Reprogramming of m6A epitranscriptome is crucial for shaping of transcriptome and proteome in response to hypoxia.

Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m6A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m6A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m6A eraser, ALKBH5. Meanwhile, expression levels of most YTH family members of m6A readers were systematically down-regulated. Transcriptome-wide analysis of m6A revealed a drastic reprogramming of m6A epitranscriptome during cellular hypoxia. Integration of m6A epitranscriptome with either RNA-seq based transcriptome analysis or mass spectrometry (LC-MS/MS) based proteome analysis of cells upon hypoxic stress revealed that reprogramming of m6A epitranscriptome reshaped the transcriptome and proteome, thereby supporting efficient generation of energy for adaption to hypoxia. Moreover, ATP production was blocked when silencing an m6A eraser, ALKBH5, under hypoxic condition, demonstrating that m6A pathway is an important regulator during hypoxic response. Collectively, our studies indicate that crosstalk between m6A and HIF1 pathway is essential for cellular response to hypoxia, providing insights into the underlying molecular mechanisms during hypoxia.

N6-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2.

A dynamic epigenome is critical for appropriate gene expression in development and health1-5. Central to this is the intricate process of transcription6-11, which integrates cellular signaling with chromatin changes, transcriptional machinery and modifications to messenger RNA, such as N6-methyladenosine (m6A), which is co-transcriptionally incorporated. The integration of these aspects of the dynamic epigenome, however, is not well understood mechanistically. Here we show that the repressive histone mark H3K9me2 is specifically removed by the induction of m6A-modified transcripts. We demonstrate that the methyltransferase METTL3/METTL14 regulates H3K9me2 modification. We observe a genome-wide correlation between m6A and occupancy by the H3K9me2 demethylase KDM3B, and we find that the m6A reader YTHDC1 physically interacts with and recruits KDM3B to m6A-associated chromatin regions, promoting H3K9me2 demethylation and gene expression. This study establishes a direct link between m6A and dynamic chromatin modification and provides mechanistic insight into the co-transcriptional interplay between RNA modifications and histone modifications.

The RNA N6-methyladenosine modification landscape of human fetal tissues.

A single genome gives rise to diverse tissues through complex epigenomic mechanisms, including N6-methyladenosine (m6A), a widespread RNA modification that is implicated in many biological processes. Here, to explore the global landscape of m6A in human tissues, we generated 21 whole-transcriptome m6A methylomes across major fetal tissues using m6A sequencing. These data reveal dynamic m6A methylation, identify large numbers of tissue differential m6A modifications and indicate that m6A is positively correlated with gene expression homeostasis. We also report m6A methylomes of long intergenic non-coding RNA (lincRNA), finding that enhancer lincRNAs are enriched for m6A. Tissue m6A regions are often enriched for single nucleotide polymorphisms that are associated with the expression of quantitative traits and complex traits including common diseases, which may potentially affect m6A modifications. Finally, we find that m6A modifications preferentially occupy genes with CpG-rich promoters, features of which regulate RNA transcript m6A. Our data indicate that m6A is widely regulated by human genetic variation and promoters, suggesting a broad involvement of m6A in human development and disease.

A high plant density reduces the ability of maize to use soil nitrogen.

Understanding the physiological changes associated with high grain yield and high N use efficiency (NUE) is important when increasing the plant density and N rate to develop optimal agronomic management. We tested the hypothesis that high plant densities resulting in crowding stress reduce the ability of plants to use the N supply post-silking, thus decreasing the grain yield and NUE. In 2013 and 2014, a field experiment, with five N-application rates and three plant densities (6.0, 7.5, and 9.0 plants m-2), was conducted in the North China Plain (NCP). The calculated maximum grain yield and agronomic use efficiency (AEN) at a density of 7.5 plants m-2 were 12.4 Mg ha-1 and 39.3 kg kg-1, respectively, which were significantly higher than the values obtained at densities of 6.0 (11.3 Mg ha-1 and 30.2 kg kg-1) and 9.0 plant m-2 (11.7 Mg ha-1 and 27.8 kg kg-1). A high plant density of 9.0 plants m-2 decreased the post-silking N accumulation, leaf N concentration and net photosynthesis, which reduced the post-silking dry matter production, resulting in a low yield and NUE. Although a relatively low grain yield was observed at a density of 9.0 plants m-2, the optimal N rate increased from 150 to 186 kg N ha-1 at a density of 7.5 plants m-2. These results indicate that high plant densities with crowding stress reduce the ability of plants to use soil N during the post-silking period, and high rate of N fertilizer was needed to increase grain yield. We conclude that selecting the appropriate plant density combined with optimal N management could increase grain yields and the NUE in the NCP.