Biology subjects

Cui, X.-L.

Publications and source records attributed to Cui, X.-L..

5 recordsLinked to original sources

bioRxiv2025

Discovery of circulating cell-free DNA 5hmC biomarkers for peritoneal metastasis in colorectal and appendiceal cancer

IntroductionPeritoneal metastases (PM) are associated with poor prognosis in patients with colorectal cancer (CRC) or appendiceal adenocarcinoma (AA), yet detection of PM is unreliable using current circulating DNA technology. Leveraging novel 5hmC-seal technology to detect ultra-low amounts of DNA in plasma, we demonstrate the feasibility of 5-hydroxymethylcytosine (5hmC) signatures derived from circulating cell-free DNA (cfDNA) as biomarkers for PM. MethodsUsing a highly sensitive and robust 5hmC sequencing approach on genomic DNA isolated from peripheral blood samples, we developed predictive models to identify biomarkers for peritoneal metastases. ResultsWe obtained genome-wide 5hmC profiles from 71 CRC/AA patients with PM, 41 without PM, and 73 non-cancer controls. Predictive models trained on genomic region 5hmC levels in patients with cancer could distinguish PM status with high sensitivity and moderate specificity (AUC 0.827, sensitivity 92.4%, specificity 46.1%). Pathway enrichment analysis identified epigenetically dysregulated cancer, cell migration, adhesion, and immune-related pathways in PM. ConclusionNovel 5hmC-Seal technology based 5hmC signatures can detect patients with peritoneal metastases from CRC and AA, albeit with reduced specificity. This study lays a foundation for future clinical assay development for PM. Statement of significanceWe demonstrate high-sensitivity detection of peritoneal metastasis in colorectal and appendiceal adenocarcinomas using 5hmC-Seal of plasma cfDNA. Earlier detection of this condition could expand curative treatments in [~]20,000 affected U.S. patients.

cancer biology↗

bioRxiv2024

Machine learning identifies cell-free DNA 5-hydroxymethylation biomarkers that detect occult colorectal cancer in PLCO Screening Trial subjects

BackgroundColorectal cancer (CRC) is a leading cause of cancer-related mortality, and CRC detection through screening improves survival rates. A promising avenue to improve patient screening compliance is the development of minimally-invasive liquid biopsy assays that target CRC biomarkers on circulating cell-free DNA (cfDNA) in peripheral plasma. In this report, we identify cfDNA biomarker candidate genes bearing the epigenetic mark 5-hydroxymethylcytosine (5hmC) that diagnose occult CRC up to 36 months prior to clinical diagnosis using the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial samples. MethodsArchived PLCO Trial plasma samples containing cfDNA were obtained from the National Cancer Institute (NCI) biorepositories. Study subjects included those who were diagnosed with CRC within 36 months of blood collection (i.e., case, n = 201) and those who were not diagnosed with any cancer during an average of 16.3 years of follow-up (i.e., controls, n = 402). Following the extraction of 3 - 8 ng cfDNA from less than 300 microliters plasma, we employed the sensitive 5hmC-Seal chemical labeling approach, followed by next-generation sequencing (NGS). We then conducted association studies and machine-learning modeling to analyze the genome-wide 5hmC profiles within training and validation groups that were randomly selected at a 2:1 ratio. ResultsDespite the technical challenges associated with the PLCO samples (e.g., limited plasma volumes, low cfDNA amounts, and long archival times), robust genome-wide 5hmC profiles were successfully obtained from these samples. Association analyses using the Cox proportional hazards models suggested several epigenetic pathways relevant to CRC development distinguishing cases from controls. A weighted Cox model, comprised of 32-associated gene bodies, showed predictive detection value for CRC as early as 24-36 months prior to overt tumor presentation, and a trend for increased predictive power was observed for blood samples collected closer to CRC diagnosis. Notably, the 5hmC-based predictive model showed comparable performance regardless of sex and self-reported race/ethnicity, and significantly outperformed risk factors such as age and obesity according to BMI (body mass index). Additionally, further improvement of predictive performance was achieved by combining the 5hmC-based model and risk factors for CRC. ConclusionsAn assay of 5hmC epigenetic signals on cfDNA revealed candidate biomarkers with the potential to predict CRC occurrence despite the absence of clinical symptoms or the availability of effective predictors. Developing a minimally-invasive clinical assay that detects 5hmC-modified biomarkers holds promise for improving early CRC detection and ultimately patient survival through higher compliance screening and earlier intervention. Future investigation to expand this strategy to prospectively collected samples is warranted.

genomics↗

bioRxiv2023

The Complexity of Functional Connectivity Profiles of the Subgenual Anterior Cingulate Cortex and Dorsal Lateral Prefrontal Cortex in Major Depressive Disorder: a DIRECT Consortium Study

BackgroundThe subgenual anterior cingulate cortex (sgACC) plays a central role in the pathophysiology of major depressive disorder (MDD), and its functional interactive profile with the left dorsal lateral prefrontal cortex (DLPFC) is associated with transcranial magnetic stimulation (TMS) treatment outcomes. Nevertheless, previous research on sgACC functional connectivity (FC) in MDD has yielded inconsistent results, partly due to small sample sizes and limited statistical power. Furthermore, calculating sgACC-FC to target TMS individually is challenging. MethodsLeveraging a large multi-site cross-sectional sample (1660 MDD patients vs. 1341 healthy controls) from Phase II of the Depression Imaging REsearch ConsorTium (DIRECT), we systematically delineated case-control difference maps of sgACC-FC. Then, we explored the potential impact of such group-level abnormality profiles on the TMS target localization and clinical efficacy. Next, we developed an MDD big data-guided individualized TMS targeting algorithm to integrate group-level statistical maps with individual-level brain activity to localize TMS targets individually. ResultsWe found an enhanced sgACC-DLPFC FC in MDD patients compared to healthy controls (HC). Such group differences altered the position of the sgACC anti-correlation peak in the left DLPFC. In two independent clinical samples, we showed that the magnitude of TMS targets case-control differences in sgACC FC was related to clinical improvement. The MDD big data-guided individualized TMS targeting algorithm may generate individualized TMS targets that are clinically superior to group-level targets. InterpretationWe reliably delineated MDD-related abnormalities of sgACC-FC profiles in a large, independently ascertained sample and demonstrated the potential impact of such case-control differences on FC-guided localization of TMS targets. FundingMinistry of Science and Technology of the Peoples Republic of China, National Natural Science Foundation of China, and Chinese Academy of Sciences

neuroscience↗

bioRxiv2021

The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates metabolism and development via translation

Ribosomal RNAs (rRNAs) have long been known to carry modifications, including numerous sites of 2O-methylation and pseudouridylation, as well as N6-methyladenosine (m6A), and N6,6-dimethyladenosine. While the functions of many of these modifications are unclear, some are highly conserved and occur in regions of the ribosome critical for mRNA decoding. Both 28S rRNA and 18S rRNA carry m6A, and while ZCCHC4 has been identified as the methyltransferase responsible for the 28S rRNA m6A site, the methyltransferase responsible for the 18S rRNA m6A site has remained uncharacterized until recently. Here, we show that the METTL5-TRMT112 complex is the methyltransferase responsible for installing m6A at position 1832 of human 18S rRNA. TRMT112 is required for the metabolic stability of METTL5, and human METTL5 mutations associated with microcephaly and intellectual disability disrupt this interaction. Loss of METTL5 in human cancer lines alters the translation of transcripts associated with mitochondrial biogenesis and function. Mettl5 knockout mice display reduced body size and evidence of metabolic defects. This m6A site is located on the 3 end of 18S rRNA, which may become surface-exposed under some circumstances and thus may play a regulatory role in translation of specific transcripts. While recent work has focused heavily on m6A modifications in mRNA and its roles in mRNA processing and translation, deorphanizing putative methyltransferase enzymes is revealing previously unappreciated regulatory roles for m6A in noncoding RNAs.

biochemistry↗

bioRxiv2018

Reduced but not Enhanced Default Mode Network Functional Connectivity in Major Depressive Disorder: Evidence from 25 Cohorts in the REST-meta-MDD Project

Major Depressive Disorder (MDD) is common and disabling, but its neural pathophysiology remains unclear. Functional brain network studies in MDD have largely had limited statistical power and data analysis approaches have varied widely. The REST-meta-MDD Project of resting-state fMRI (R-fMRI) addresses these issues. The 25 research groups in China composing the REST-meta-MDD Project contributed R-fMRI data of 1,300 patients with MDD and 1,128 normal controls (NCs). The data were preprocessed locally with a standardized protocol prior to aggregated group analyses. We focused on functional connectivity (FC) within the default mode network (DMN), frequently reported to show increased FC in MDD. We found decreased instead of increased DMN FC when comparing 848 MDDs with 794 NCs from 17 sites after data exclusion. We found FC reduction only in recurrent MDD, not in first-episode drug-naive MDD. Decreased DMN FC was associated with medication usage but not with MDD duration. DMN FC was also positively related to symptom severity but only in recurrent MDDs. Exploratory analyses also revealed alterations of local intrinsic activity in MDD. We confirmed the key role of DMN in MDD but found reduced rather than increased FC within the DMN. Future studies should test whether decreased DMN FC mediates treatment response. This manuscript announces the publicly available resting-state fMRI indices of the REST-meta-MDD consortium shared via the R-fMRI Maps Project.\n\nSIGNIFICANCE STATEMENTFunctional connectivity within the default mode network in major depressive disorder patients has been frequently reported abnormal but with contradicting directions in previous small sample size studies. By creating the REST-meta-MDD consortium containing neuroimaging data of 1,300 depressed patients and 1,128 normal controls from 25 research groups in China, we found decreased default mode network functional connectivity in depressed patients, driven by patients with recurrent depression, and associated with current medication treatment but not with disease duration. These findings suggest that default mode network functional connectivity remains a prime target for understanding the pathophysiology of depression, with particular relevance to revealing mechanisms of effective treatments.

neuroscience↗