Yanqiang Ding

The role of RNA N ⁶ -methyladenoine (m ⁶ A) eraser AlkB homologue 5 (ALKBH5) in colorectal cancer (CRC) stem cells (CSCs) is unclear. Here, we find that ALKBH5 expression positively correlates with CSC markers in CRC patients. ALKBH5 induces self-renewal and stemness markers in colorectal CSCs and patient-derived organoids (PDOs). Colon-stem cell specific Alkbh5 knockin accelerates carcinogen-induced CRC, while tumorigenesis is attenuated in colon-stem cell specific Alkbh5 knockout mice. Integrated RNA-seq, MeRIP-seq and Ribo-seq reveal FAM84A as an ALKBH5 target. ALKBH5 demethylates m ⁶ A-modified FAM84A mRNA, causing mRNA decay and reduced expression. Mechanistically, we show that FAM84A represses CSCs by interacting with β-catenin and promoting β-catenin ubiquitination and degradation. By boosting CSCs, ALKBH5 overexpression elicit chemoresistance in CSCs, PDOs and transgenic mice. Targeting of ALKBH5 by knockout or VNPs-siALKBH5 synergizes with chemotherapy to trigger tumor regression in CSCs-/PDOs-derived xenografts and ALKBH5 knockout mice. Together, we reveal that ALKBH5 is essential for colorectal CSCs and is a therapeutic target for overcoming CRC chemoresistance.

Terrestrialization is an important evolutionary process that plants experienced. However, little is known about how land plants acquired aquatic growth behaviors. Here, we integrate multiproxy evidence to elucidate the evolution of the aquatic plant duckweed. Three genera of duckweeds show chronologically gradual degeneration in root structure and stomatal function and a decrease in lignocellulose content, accompanied by the contraction of relevant gene families and/or a decline in their transcription levels. The number of genes in main phytohormone pathways is also gradually decreased. The coordinated action of genes involved in auxin signaling and rhizoid development causes a gradual decrease in adventitious roots. Additionally, the significant expansion of the flavonoid pathway is related to the adaptation of duckweeds to floating growth. This study reconstructs the evolutionary history of duckweeds, tracing its journey from land back to water — a reverse trajectory of early land plants.

The high host genetic background of tissue biopsies hinders the application of shotgun metagenomic sequencing in characterizing the tissue microbiota. We proposed an optimized method that removed host DNA from colon biopsies and examined the effect on metagenomic analysis. Human or mouse colon biopsies were divided into two groups, with one group undergoing host DNA depletion and the other serving as the control. Host DNA was removed through differential lysis of mammalian and bacterial cells before sequencing. The impact of host DNA depletion on microbiota was compared based on phylogenetic diversity analyses and regression analyses. Removing host DNA enhanced bacterial sequencing depth and improved species discovery, increasing bacterial reads by 2.46 ± 0.20 folds while reducing host reads by 6.80% ± 1.06%. Moreover, 2.40 times more of bacterial species were detected after host DNA depletion. This was confirmed from mouse colon tissues, increasing bacterial reads by 5.46 ± 0.42 folds while decreasing host reads by 10.2% ± 0.83%. Similarly, significantly more bacterial species were detected in the mouse colon tissue upon host DNA depletion (P < 0.001). Furthermore, an increased microbial richness was evident in the host DNA-depleted samples compared with non-depleted controls in human colon biopsies and mouse colon tissues (P < 0.001). Our optimized method of host DNA depletion improves the sensitivity of shotgun metagenomic sequencing in bacteria detection in the biopsy, which may yield a more accurate taxonomic profile of the tissue microbiota and identify bacteria that are important for disease initiation or progression.

The consistency of the associations between gastric mucosal microbiome and gastric cancer across studies remained unexamined. We aimed to identify universal microbial signatures in gastric carcinogenesis through a meta-analysis of gastric microbiome from multiple studies. Compositional and ecological profiles of gastric microbes across stages of gastric carcinogenesis were significantly altered. Meta-analysis revealed that opportunistic pathobionts Fusobacterium, Parvimonas, Veillonella, Prevotella and Peptostreptococcus were enriched in GC, while commensals Bifidobacterium, Bacillus and Blautia were depleted in comparison to SG. The co-occurring correlation strengths of GC-enriched bacteria were increased along disease progression while those of GC-depleted bacteria were decreased. Eight bacterial taxa, including Veillonella, Dialister, Granulicatella, Herbaspirillum, Comamonas, Chryseobacterium, Shewanella and Helicobacter, were newly identified by this study as universal biomarkers for robustly discriminating GC from SG, with an area under the curve (AUC) of 0.85. Moreover, H. pylori-positive samples exhibited reduced microbial diversity, altered microbiota community and weaker interactions among gastric microbes. Our meta-analysis demonstrated comprehensive and generalizable gastric mucosa microbial features associated with histological stages of gastric carcinogenesis, including GC associated bacteria, diagnostic biomarkers, bacterial network alteration and H. pylori influence.