Jingzhu Guo

Background: Down syndrome (DS), the most prevalent chromosomal disorder caused by trisomy 21, manifests intellectual disability and cognitive dysfunction. Cumulative studies confirm epigenetic pathways including DNA methylation and non-coding RNAs drive DS pathological progression. Histone post-translational modifications (PTMs) are core epigenetic regulators of fetal brain development. However, genome-wide PTM alterations and their downstream functions in fetal DS brains remain poorly characterized, leaving a key gap in revealing epigenetic mechanisms underlying DS neurodevelopmental defects. To address this, we aimed to establish the first comprehensive landscape of histone PTMs in fetal DS cortex and investigate whether specific PTM changes contribute to aberrant neurodevelopmental gene expression. Methods: Fetal cortexs from control and DS groups were subjected to global histone modification profiling via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). We detected mono-, di-, and tri-methylation, acetylation, homocysteinylation and malonylation on all four core histones (H2A, H2B, H3, H4). Chromatin immunoprecipitation sequencing (ChIP-seq) was used to map genomic binding profiles of H3 lysine 79 acetylation (H3K79ac). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to quantify mRNA levels of candidate neurodevelopmental genes. Results: HPLC-MS/MS analysis identified 172 distinct histone PTMs in control fetal cortices and 168 PTMs in DS fetal cortical samples. Quantitative comparison of 22 quantifiable histone PTMs revealed that H3K79ac showed the most prominent reduction in DS samples, with a 34% decrease (PTNFSF13B, NXPH1 and CAMK4. Correspondingly, qRT-PCR revealed aberrant transcription levels of these three genes in DS fetal cortices. Conclusions: This study establishes the first quantitative landscape of histone PTMs in in DS fetal cortical tissues. We demonstrate that depleted H3K79ac acts as a candidate epigenetic driver of DS neuropathology by disrupting the transcription of critical neurodevelopmental genes. This work reveals a novel epigenetic mechanism and a promising therapeutic target for DS-related neurodevelopmental disorders.

Cognitive impairment is a significant health problem worldwide, closely associated with the status of gut microbiota. Our recent research has revealed the Blautia faecis and Blautia massiliensis exhibit opposing associations with cognitive function in children with Down syndrome clinically characterized by cognitive dysfunction. However, the role and mechanisms of Blautia faecis and Blautia massiliensis in cognitive function remain unknown. Therefore, we gavaged C57BL/6 male mice with commercially available Blautia faecis and Blautia massiliensis for 3 weeks and assessed cognitive function using the novel object recognition and Y-maze test. Blautia faecis administration impaired cognitive performance, whereas Blautia massiliensis treatment improved it, with these effects observed predominantly in the absence of antibiotic pretreatment. Furthermore, we observed that administration of Blautia faecis increased the number of microglia, resulting in a twofold increase in cell count relative to WT control. Hippocampal pro-inflammatory cytokines were significantly upregulated in the Blautia faecis group, while Blautia massiliensis suppressed these neuroinflammatory responses. Notably, Blautia massiliensis produces approximately six times more acetate than Blautia faecis . Consequently, our findings indicate that Blautia massiliensis enhances cognitive function whereas Blautia faecis impairs it, and we speculate that differential acetate production may contribute to these opposing effects.

Background: Increasing evidence suggests that lncRNA (Long non‐coding RNA, lncRNA)‐mediated ceRNA (competing endogenous RNA, ceRNA) networks are involved in the occurrence and progression of colorectal cancer (CRC). However, the roles of the lncRNA–miRNA–mRNA ceRNA network in distant metastasis of CRC are still unclear.Methods: In this study, we constructed a specific ceRNA network to identify potential biomarkers and therapeutic targets for distant metastasis of CRC. Specifically, RNA‐Seq data from The Cancer Genome Atlas (TCGA) were used to screen for differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) related to metastasis. After validation and selection by qRT–PCR and univariate and multivariate analysis of the metastasis‐ and prognosis‐related lncRNAs, the regulated microRNAs (miRNAs) and coexpressed mRNAs were used to construct a ceRNA network for distant metastasis of CRC.Results: Two key distant metastasis‐related DElncRNAs, AP002498.1 and LINC01871, were identified by univariate and multivariate analysis in combination with analyses of clinical data and expression levels. Furthermore, lncRNA‐associated ceRNA subnetworks were constructed from the predicted miRNAs and 13 coexpressed DEmRNAs (SERPINA1, ITLN1, REG4, L1TD1, IGFALS, MUC5B, CIITA, CXCL9, CXCL10, GBP4, GNLY, IDO1, and NOS2). The AP002498.1‐ and LINC01871‐associated ceRNA subnetworks regulated the expression of the target genes SERPINA1 and MUC5B and GNLY, respectively, through the associated miRNAs.Conclusion: The DElncRNA AP002498.1 and the LINC01871/miR‐4644 and miR‐185‐5p/GNLY axes were identified as being closely associated with distant metastasis and could represent independent prognostic biomarkers or therapeutic targets in colorectal adenocarcinoma.

Histone acetylation and mitochondrial function contribute importantly to neural differentiation, which is critically associated with neurodevelopmental disorders such as Down Syndrome (DS). However, whether and how histone acetylation regulates mitochondrial function and further affects neural differentiation has not been well described. In this study, when treated with retinoid acid (RA), the human neuroblastoma SH-SY5Y cell line was used as a neural differentiation model. We found that the acetylation of histone H3, especially H3 lysine 14 acetylation (H3K14ac), and mitochondrial function, including biogenesis and electron transport chain, were enhanced during neural differentiation. Specific inhibition of histone acetyltransferases (HATs) induced neural differentiation deficits, accompanied by downregulation of mitochondrial function. Furthermore, RA receptors (RARs) interacting with HATs were involved in the increased H3K14ac and the enhanced mitochondrial function during the neural differentiation process. Finally, receptor-interacting protein 140 (RIP140), a co-repressor of RARs, was also involved in regulating histone acetylation. RIP140 overexpression inhibited histone acetylation and mediated negative feedback on target genes which are involved in RA signaling. These findings evidenced that when interacting with RARs which had been negatively regulated by RIP140, RA promoted neural differentiation by promoting H3K14ac and enhanced mitochondrial function. This provides a molecular foundation for further investigations into abnormal neural development.

Purpose Down syndrome (DS) is linked to a higher prevalence of obstructive sleep apnea (OSA) than in the general population, which in turn contributes to worse cognitive impairment in DS. However, the shared pathogenic mechanisms for DS and OSA remain incompletely illustrated. This study was designed to decipher the genetic cross-talk between DS and OSA by bioinformatics approach. Methods Transcriptomic datasets of DS (GSE59630) and OSA (GSE135917) were accessed from the Gene Expression Omnibus (GEO) repository. After screening out the common differentially expressed genes (DEGs) for DS and OSA, gene ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out. A protein–protein interaction (PPI) network was then constructed to determine essential modules and hub genes. Finally, based on hub genes, transcriptional factor (TF)–gene interaction and TF-miRNA regulatory networks were constructed. Results DS and OSA showed 229 DEGs. Functional analyses revealed how oxidative stress and inflammatory response were critical in the progression of DS and OSA. Ten significant hub genes were identified, including TLR4, SOD1, IGF1, FGF2, NFE2L2, PECAM1, S100A8, S100A9, FCGR3A, and KCNA1, which were candidate targets for DS and OSA. Conclusions We found that DS and OSA display similarities in their pathogenesis. Key genes and signaling pathways revealed to be in common between the two conditions could lead us to new therapeutic targets for DS and OSA.

Introduction: Down syndrome (DS), the presence of a supernumerary chromosome 21, is associated with cognitive dysfunction caused by early neurodegenerative processes. Alterations in the gut microbiota were observed in Chinese children with DS, and the genus Blautia was associated with cognitive function in these children. Therefore, it is crucial to understand the detailed composition of this group at the species level and to explore the effect of specific species on cognitive function.Methods: In this study, Blautia-specific amplicon sequencing was conducted to identify the specific Blautia species in 15 children with DS and 15 matched healthy children.Results: The taxonomic analyses suggested that the Blautia taxa were clustered by disease status. The diversity of Blautia at the species level differed between DS patients and healthy controls, with the abundances of Blautia massiliensis and Blautia argi decreasing in DS children, while Blautia faecis was increased. Acetic acid, one of the metabolites of Blautia, was significantly reduced in the DS group. Of particular interest, Kyoto Encyclopaedia of Genes and Genomes analysis revealed decreased modules related to starch and sucrose metabolism and glycolysis. In addition, B. argi was positively related to DS cognitive scores, and B. faecis was negatively related to cognitive function, implying its role on the DS cognitive impairments. Discussion: Our study has important implications for understanding the important effects of specific species of Blautia on cognitive function and thus possibly provides a new strategy for future studies of cognitive improvement in individuals with DS.

Data evaluating changes in bone mineral density (BMD) in Down syndrome (DS) individuals remains controversial. Therefore, we conducted a systematic review and meta-analysis to better understand associations between BMD and DS. A systematic literature search of PubMed, EMBASE, Web of Science, and the Cochrane Library up until 1st January 2021 was conducted. We used the keywords “bone mineral density” and “Down Syndrome.” Fifteen studies were included. Overall, our results showed a significant decrease in BMD of total body (TB BMD) [MD = − 0.18; 95% CI (− 0.23 and − 0.12), P < 0.00001, I² = 89%], total hip (TH BMD) [MD = − 0.12; 95% CI (− 0.15 and − 0.10), P < 0.00001, I² = 0%], lumbar spine (LS BMD) [MD = − 0.12; 95% CI (− 0.14 and − 0.09), P < 0.00001, I² = 18%], and femoral neck (FN BMD) [MD = − 0.08; 95% CI (− 0.10 and − 0.06), P < 0.00001, I² = 0%] in DS individuals when compared with controls. Moreover, the volumetric BMD of lumbar spine (LS vBMD) [MD = − 0.01; 95% CI (− 0.02 and − 0.01), P = 0.0004, I² = 19%] also showed a decreasing tendency while the volumetric BMD of the femoral neck (FN vBMD) [MD = 0.01; 95% CI (0.00 and 0.02), P = 0.02, I² = 0%] was elevated in DS individuals versus controls. These findings demonstrated that individuals with DS had a decreased total and regional (TH, LS, and FN) BMD when compared with the general population. Additionally, when BMD was adjusted for skeletal volume, LS vBMD was also lower, while FN vBMD was elevated in DS individuals versus controls.

Down's syndrome (DS), a common chromosomal disease caused by chromosome 21 trisomy, is the main cause of cognitive impairment in children worldwide. Emerging evidence suggests that the microbiota–gut–brain axis plays a potential role in cognitive impairment. However, data regarding gut microbiota alterations in DS patients remain scarce, especially data from children with DS. This case–control study was conducted to explore the gut microbiota composition in Chinese DS children. Additionally, the potential association between gut microbiota and cognitive function in DS was evaluated. Microbiota communities in the feces of 15 DS subjects and 15 matched controls were investigated using high-throughput Illumina Miseq sequencing targeting the V3–V4 region of 16S rRNA gene. The relationships between gut microbiota composition and DS cognitive function scores were analyzed. The structure and richness of the gut microbiota differed between DS patients and healthy controls. The abundance of Acidaminococcaceae was decreased in DS patients. Moreover, the Kyoto Encyclopedia of Genes and Genomes analysis showed increased modules related to peptidases and pyrimidine metabolism. Overall, we confirmed that gut microbiota alterations occurred in Chinese patients with DS. Additionally, the fecal microbiota was closely related to DS cognitive impairment. Larger cohorts are needed to confirm these findings and to clarify the mechanisms involved. Elucidating these novel findings in the field of microbiota-gut-brain axis will provide a promising strategy for future studies of DS cognitive impairment.