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Engineering natural microbiomes for biotechnological applications remains challenging, as metabolic interactions within microbiomes are largely unknown, and practical principles and tools for microbiome engineering are still lacking. Here, we present a combinatory top-down and bottom-up framework to engineer natural microbiomes for the construction of function-enhanced synthetic microbiomes. We show that application of herbicide and herbicide-degrader inoculation drives a convergent succession of different natural microbiomes toward functional microbiomes (e.g., enhanced bioremediation of herbicide-contaminated soils). We develop a metabolic modeling pipeline, SuperCC, that can be used to document metabolic interactions within microbiomes and to simulate the performances of different microbiomes. Using SuperCC, we construct bioremediation-enhanced synthetic microbiomes based on 18 keystone species identified from natural microbiomes. Our results highlight the importance of metabolic interactions in shaping microbiome functions and provide practical guidance for engineering natural microbiomes. Engineering natural microbiomes for biotechnological applications remains challenging. Here, the authors present a combinatory top-down and bottom-up framework to engineer natural microbiomes for the construction of function-enhanced synthetic microbiomes.

N6-methyladenosine (m 6 A), the most abundant modification of mRNA, is essential for normal development and dysregulation promotes cancer. m 6 A is highly enriched in the 3’ untranslated region (UTR) of a large subset of mRNAs to influence mRNA stability and/or translation. However, the mechanism responsible for the observed m 6 A distribution remains enigmatic. Here we find the exon junction complex shapes the m 6 A landscape by blocking METTL3-mediated m 6 A modification close to exon junctions within coding sequence (CDS). Depletion of EIF4A3, a core component of the EJC, causes increased METTL3 binding and m 6 A modification of short internal exons, and sites close to exon-exon junctions within mRNA. Reporter gene experiments further support the role of splicing and EIF4A3 deposition in controlling m 6 A modification via the local steric blockade of METTL3. Our results explain how characteristic patterns of m 6 A mRNA modification are established and uncover a role of the EJC in shaping the m 6 A epitranscriptome. Here the authors show the exon junction complex (EJC) component, EIF4A3, locally restricts METTL3- mediated mRNA methylation at exon junctions to explain the observed widespread enrichment of m6A modification in 3’ untranslated regions.

Besides genome editing, CRISPR-Cas12a has recently been used for DNA detection applications with attomolar sensitivity but, to our knowledge, it has not been used for the detection of small molecules. Bacterial allosteric transcription factors (aTFs) have evolved to sense and respond sensitively to a variety of small molecules to benefit bacterial survival. By combining the single-stranded DNA cleavage ability of CRISPR-Cas12a and the competitive binding activities of aTFs for small molecules and double-stranded DNA, here we develop a simple, supersensitive, fast and high-throughput platform for the detection of small molecules, designated CaT-SMelor ( C RISPR-Cas12a- and aT F-mediated s mall m ol e cu l e detect or ). CaT-SMelor is successfully evaluated by detecting nanomolar levels of various small molecules, including uric acid and p -hydroxybenzoic acid among their structurally similar analogues. We also demonstrate that our CaT-SMelor directly measured the uric acid concentration in clinical human blood samples, indicating a great potential of CaT-SMelor in the detection of small molecules. Bacterial allosteric transcription factors can sense and respond to a variety of small molecules. Here the authors present CaT-SMelor which uses Cas12a and allosteric transcription factors to detect small molecules in the nanomolar range.

Lipid-like nanoparticles (LNPs) have potential as non-viral delivery systems for mRNA therapies. However, repeated administrations of LNPs may lead to accumulation of delivery materials and associated toxicity. To address this challenge, we have developed biodegradable lipids which improve LNPs clearance and reduce toxicity. We modify the backbone structure of Dlin-MC3-DMA by introducing alkyne and ester groups into the lipid tails. We evaluate the performance of these lipids when co-formulated with other amine containing lipid-like materials. We demonstrate that these formulations synergistically facilitate robust mRNA delivery with improved tolerability after single and repeated administrations. We further identify albumin-associated macropinocytosis and endocytosis as an ApoE-independent LNP cellular uptake pathway in the liver. Separately, the inclusion of alkyne lipids significantly increases membrane fusion to enhance mRNA release, leading to synergistic improvement of mRNA delivery. We believe that the rational design of LNPs with multiple amine-lipids increases the material space for mRNA delivery. Lipid-like nanoparticles have applications as non-viral delivery systems for mRNA. Here, the authors develop biodegradable lipids with improved clearance and reduced toxicity.

Various methyltransferases and demethylases catalyse methylation and demethylation of N 6 -methyladenosine (m6A) and N 6 ,2′-O-dimethyladenosine (m6Am) but precise methylomes uniquely mediated by each methyltransferase/demethylase are still lacking. Here, we develop m6A-Crosslinking-Exonuclease-sequencing (m6ACE-seq) to map transcriptome-wide m6A and m6Am at quantitative single-base-resolution. This allows for the generation of a comprehensive atlas of distinct methylomes uniquely mediated by every individual known methyltransferase or demethylase. Our atlas reveals METTL16 to indirectly impact manifold methylation targets beyond its consensus target motif and highlights the importance of precision in mapping PCIF1-dependent m6Am. Rather than reverse RNA methylation, we find that both ALKBH5 and FTO instead maintain their regulated sites in an unmethylated steady-state. In FTO’s absence, anomalous m6Am disrupts snRNA interaction with nuclear export machinery, potentially causing aberrant pre-mRNA splicing events. N 6 -methyladenosine (m6A) and N 6 ,2′-O-dimethyladenosine (m6Am) are eukaryotic mRNA modifications. Here the authors develop m6A-Crosslinking-Exonuclease-sequencing to map quantitative methylome changes at single-base-resolution after individually knocking out each known methyltransferase or demethylase.

Parabacteroides distasonis ( P. distasonis ) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis. Parabacteroides distasonis ( P. distasonis ), part of the gut microbiome, was reported to play a role in diabetes, colorectal cancer and inflammatory bowel disease. Here the authors report that P. distasonis ameliorates liver fibrosis in studies with male mice, potentially via altered bile acid metabolism and hepatocyte pyroptosis.

Prognostic genes are key molecules informative for cancer prognosis and treatment. Previous studies have focused on the properties of individual prognostic genes, but have lacked a global view of their system-level properties. Here we examined their properties in gene co-expression networks for four cancer types using data from ‘The Cancer Genome Atlas’. We found that prognostic mRNA genes tend not to be hub genes (genes with an extremely high connectivity), and this pattern is unique to the corresponding cancer-type-specific network. In contrast, the prognostic genes are enriched in modules (a group of highly interconnected genes), especially in module genes conserved across different cancer co-expression networks. The target genes of prognostic miRNA genes show similar patterns. We identified the modules enriched in various prognostic genes, some of which show cross-tumour conservation. Given the cancer types surveyed, our study presents a view of emergent properties of prognostic genes. Many studies provide evidence of genes that are associated with cancer prognosis but a global view of these genes is lacking. Using data from ‘The Cancer Genome Atlas’, Yang et al. investigate the network properties of prognostic genes and show that these genes tend to be within highly interconnected groups but not the most connected nodes in the gene co-expression network.

The mechanisms underlying gene repression and silencers are poorly understood. Here we investigate the hypothesis that H3K27me3-rich regions of the genome, defined from clusters of H3K27me3 peaks, may be used to identify silencers that can regulate gene expression via proximity or looping. We find that H3K27me3-rich regions are associated with chromatin interactions and interact preferentially with each other. H3K27me3-rich regions component removal at interaction anchors by CRISPR leads to upregulation of interacting target genes, altered H3K27me3 and H3K27ac levels at interacting regions, and altered chromatin interactions. Chromatin interactions did not change at regions with high H3K27me3, but regions with low H3K27me3 and high H3K27ac levels showed changes in chromatin interactions. Cells with H3K27me3-rich regions knockout also show changes in phenotype associated with cell identity, and altered xenograft tumor growth. Finally, we observe that H3K27me3-rich regions-associated genes and long-range chromatin interactions are susceptible to H3K27me3 depletion. Our results characterize H3K27me3-rich regions and their mechanisms of functioning via looping. Mechanisms underlying gene repression and silencers remain poorly understood. Here the authors investigate the role of H3K27me3-rich regions in the genome, as defined from clusters of H3K27me3 peaks, in regulating gene expression via looping.

Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3′tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs ( RPS28 and RPS15 ) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer. A 22-nucleotide fragment of a transfer RNA regulates translation by binding to the mRNA of a ribosomal protein and increasing its expression, and downregulation of the fragment in patient-derived liver tumour cells reduces tumour growth in mice. An anticancer tRNA fragment The functional roles of small RNA fragments derived from tRNAs are not well known, but evidence is growing that some play a part in various cellular processes. Mark Kay and colleagues show that a 22-nucleotide fragment from the 3′ end of leucine tRNA can regulate translation. The fragment binds to the mRNA of a ribosomal protein to upregulate its expression. When this interaction is suppressed in human cells in culture, cell death occurs. Decreasing the levels of the tRNA fragment with an antisense oligonucleotide can slow the growth of liver tumours in mice. Technologies aimed at reducing expression of this tRNA fragment might have utility in treating cancer.

Composition of gut bacteria and serum metabolites in young, obese individuals is partially restored following weight loss surgery, including Bacteroides thetaiotaomicron , which decreases serum glutamate levels and fat mass gain in mice. Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron , a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.