Objective: To demonstrate the type of CEBPA gene mutations among patients with acute myeloid leukemia (AML), clinical characteristics, and prognostic effect on patient outcomes. Methods: Demographic data, clinical features, laboratory characteristics, and data about treatment and follow-up of 57 patients with CEBPA mutated AML diagnosed at Peking Union Medical College Hospital between April 2016 and November 2022 were collected and analyzed. Results: In total, 57 patients with CEBPA mutation accounted for 16.1% of all the 353 patients with AML, among which 28 patients had CEBPA-bZIPinf and 29 had CEBPA-other. Compared with the CEBPA-other group, the CEBPA-bZIPinf group was younger (54 vs 64 years, P=0.010), de novo AML was more common (P=0.001), and the level of bone marrow blast was higher (68.0% vs 36.3%, P=0.001). Moreover, 24 patients from the CEBPA-bZIPinf group and 19 from the CEBPA-other group received chemotherapy. The one-course complete remission (CR) rate of the CEBPA-bZIPinf group was significantly higher than that of the CEBPA-other (87.5% vs 47.4%, P=0.010) and CEBPA-wt (87.5% vs 50.3%, P=0.002) groups. After a median follow-up of 11 months, the median OS of the CEBPA-bZIPinf group was significantly longer than that of the CEBPA-wt group (not reached vs 22.1 months, P=0.012) . Conclusion: CEBPA-bZIPinf mutated AML is a unique clinical entity, with a younger age of diagnosis, better response to chemotherapy, and better prognosis.
目的： 探讨携带CEBPA基因突变的急性髓系白血病（AML）患者的突变类型、临床特点和突变对生存结局的影响。 方法： 回顾性分析2016年4月至2022年11月期间北京协和医院确诊的57例伴有CEBPA基因突变的AML患者的人口学信息、临床表现、实验室检查结果、治疗以及生存数据。 结果： 57例CEBPA基因突变患者占同期所有353例AML患者的16.1%，其中bZIP区域框内突变（CEBPA-bZIPinf）28例，其余CEBPA基因突变（CEBPA-other）29例。与CEBPA-other患者相比，CEBPA-bZIPinf患者更年轻（54岁对64岁，P＝0.010），原发性AML更常见（P＝0.001），骨髓原始细胞比例更高（68.0%对36.3%，P＝0.001）。CEBPA-bZIPinf及CEBPA-other患者分别有24例和19例接受化疗，CEBPA-bZIPinf患者的1个疗程完全缓解率显著高于CEBPA-other（87.5%对47.4%，P＝0.010）及CEBPA野生型（87.5%对50.3%，P＝0.002）患者。中位随访11个月，CEBPA-bZIPinf患者的中位总生存期明显长于CEBPA野生型患者（未达到对22.1个月，P＝0.012）。 结论： CEBPA-bZIPinf突变的AML患者具有独特的临床特征，对化疗的反应更好，预后更佳。.

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an epigenetic regulator that plays critical roles in tumours. However, the DNA methylation alteration patterns driven by UHRF1 and the related differentially expressed tumour-related genes remain unclear. In this study, a UHRF1-shRNA MCF-7 cell line was constructed, and whole-genome bisulfite sequencing and RNA sequencing were performed. The DNA methylation alteration landscape was elucidated, and DNA methylation-altered regions (DMRs) were found to be distributed in both gene bodies and adjacent regions. The DMRs were annotated and categorized into 488 hypermethylated/1696 hypomethylated promoters and 1149 hypermethylated/5501 hypomethylated gene bodies. Through an integrated analysis with the RNA sequencing data, 217 methylation-regulated upregulated genes and 288 downregulated genes were identified, and these genes were primarily enriched in nervous system development and cancer signalling pathways. Further analysis revealed 21 downregulated oncogenes and 15 upregulated TSGs. We also showed that UHRF1 silencing inhibited cell proliferation and migration and suppressed tumour growth in vivo. Our study suggested that UHRF1 and the oncogenes or TSGs it regulates might serve as biomarkers and targets for breast cancer treatment.

BACKGROUND: Acute myeloid leukemia with normal cytogenetics (CN-AML) represents a heterogeneous group having diverse genetic mutations. Understanding the significance of each of these mutations is necessary. In this study, we evaluated the prognostic role of MN1 expression in adult CN-AML patients.
METHODS: One hundred and sixty-three de-novo adult AML patients were evaluated for MN1 expression by real-time PCR. MN1 expression was correlated with the clinical characteristics of the patients and their outcomes.
RESULTS: Higher MN1 expression was associated with NPM1 wild-type (p<0.0001), CD34 positivity (p=0.006), and lower clinical remission rate (p=0.027). FLT3-ITD and CEBPA mutations had no association with MN1 expression. On survival analysis, a high MN1 expression was associated with poor event-free survival (Hazard Ratio 2.47, 95% Confidence Interval: 1.42-4.3; p<0.0001) and overall survival (Hazard Ratio 4.18, 95% Confidence Interval: 2.17-8.08; p<0.0001). On multivariate analysis, the MN1 copy number emerged as an independent predictor of EFS (p<0.0001) and OS (p<0.0001).
CONCLUSIONS: MN1 expression is an independent predictor of outcome in CN-AML.

BACKGROUND: Previous studies have shown that peptides encoded by noncoding RNAs (ncRNAs) can be used as peptide drugs to alleviate diseases. We found that microRNA-31 (miR-31) is involved in the regulation of hypertension and that the peptide miPEP31, which is encoded by the primary transcript of miR-31 (pri-miR-31), can inhibit miR-31 expression. However, the role and mechanism of miPEP31 in hypertension have not been elucidated.
METHODS: miPEP31 expression was determined by western blot analysis. miPEP31-deficient mice (miPEP31-/-) were used, and synthetic miPEP31 was injected into Ang II-induced hypertensive mice. Blood pressure was monitored through the tail-cuff method. Histological staining was used to evaluate renal damage. Regulatory T (Treg) cells were assessed by flow cytometry. Differentially expressed genes were analysed through RNA sequencing. The transcription factors were predicted by JASPAR. Luciferase reporter and electrophoretic mobility shift assays (EMSAs) were used to determine the effect of pri-miR-31 on the promoter activity of miPEP31. Images were taken to track the entry of miPEP31 into the cell.
RESULTS: miPEP31 is endogenously expressed in target organs and cells related to hypertension. miPEP31 deficiency exacerbated but exogenous miPEP31 administration mitigated the Ang II-induced systolic blood pressure (SBP) elevation, renal impairment and Treg cell decreases in the kidney. Moreover, miPEP31 deletion increased the expression of genes related to Ang II-induced renal fibrosis. miPEP31 inhibited the transcription of miR-31 and promoted Treg differentiation by occupying the Cebpα binding site. The minimal functional domain of miPEP31 was identified and shown to regulate miR-31.
CONCLUSIONS: miPEP31 was identified as a potential therapeutic peptide for treating hypertension by promoting Treg cell differentiation in vivo. Mechanistically, we found that miPEP31 acted as a transcriptional repressor to specifically inhibit miR-31 transcription by competitively occupying the Cebpα binding site in the pri-miR-31 promoter. Our study highlights the significant therapeutic effect of miPEP31 on hypertension and provides novel insight into the role and mechanism of miPEPs.

Leukemias with ambiguous lineage comprise several loosely defined entities, often without a clear mechanistic basis. Here, we extensively profile the epigenome and transcriptome of a subgroup of such leukemias with CpG Island Methylator Phenotype. These leukemias exhibit comparable hybrid myeloid/lymphoid epigenetic landscapes, yet heterogeneous genetic alterations, suggesting they are defined by their shared epigenetic profile rather than common genetic lesions. Gene expression enrichment reveals similarity with early T-cell precursor acute lymphoblastic leukemia and a lymphoid progenitor cell of origin. In line with this, integration of differential DNA methylation and gene expression shows widespread silencing of myeloid transcription factors. Moreover, binding sites for hematopoietic transcription factors, including CEBPA, SPI1 and LEF1, are uniquely inaccessible in these leukemias. Hypermethylation also results in loss of CTCF binding, accompanied by changes in chromatin interactions involving key transcription factors. In conclusion, epigenetic dysregulation, and not genetic lesions, explains the mixed phenotype of this group of leukemias with ambiguous lineage. The data collected here constitute a useful and comprehensive epigenomic reference for subsequent studies of acute myeloid leukemias, T-cell acute lymphoblastic leukemias and mixed-phenotype leukemias.

Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC.

BACKGROUND: Overweight, often known as obesity, is the abnormal and excessive accumulation of fat that exposes the health of a person at risk by increasing the likelihood that they may experience many chronic conditions. Consequently, obesity has become a global health threat, presenting serious health issues, and attracting a lot of attention in the healthcare profession and the scientific community.
METHODS: This study aims to explore the anti-adipogenic properties of 7-MEGA™ in an attempt to address obesity, using both in vitro and in vivo research. The effects of 7MEGA™ at three distinct concentrations were investigated in obese mice who were given a high-fat diet (HFD) and 3T3-L1 adipocytes.
RESULTS: 7MEGA™ decreased the total fat mass, overall body weight, and the perirenal and subcutaneous white adipose tissue (PWAT and SWAT) contents in HFD mice. Additionally, 7MEGA™ showed promise in improving the metabolic health of individuals with obesity and regulate the levels of insulin hormone, pro-inflammatory cytokines and adipokines. Furthermore, Peroxisome proliferator-activated receptors (PPAR) α and γ, Uncoupling Protein 1 (UCP-1), Sterol Regulatory Element-Binding Protein 1 (SREBP-1), Fatty Acid-Binding Protein 4 (FABP4), Fatty Acid Synthase (FAS), Acetyl-CoA Carboxylase (ACC), Stearoyl-CoA Desaturase-1 (SCD-1) and CCAAT/Enhancer-Binding Protein (C/EBPα) were among the adipogenic regulators that 7MEGA™ could regulate.
CONCLUSIONS: In summary, this study uncovered that 7MEGA™ demonstrates anti-adipogenic and anti-obesity effects, suggesting its potential in combating obesity.

DNA methylation maintenance is essential for cell fate inheritance. In differentiated cells, this involves orchestrated actions of DNMT1 and UHRF1. In mice, the high-affinity binding of DPPA3 to the UHRF1 PHD finger regulates UHRF1 chromatin dissociation and cytosolic localization, which is required for oocyte maturation and early embryo development. However, the human DPPA3 ortholog functions during these stages remain unclear. Here, we report the structural basis for human DPPA3 binding to the UHRF1 PHD finger. The conserved human DPPA3 85VRT87 motif binds to the acidic surface of UHRF1 PHD finger, whereas mouse DPPA3 binding additionally utilizes two unique α-helices. The binding affinity of human DPPA3 for the UHRF1 PHD finger was weaker than that of mouse DPPA3. Consequently, human DPPA3, unlike mouse DPPA3, failed to inhibit UHRF1 chromatin binding and DNA remethylation in Xenopus egg extracts effectively. Our data provide novel insights into the distinct function and structure of human DPPA3.

Blackberries (Rubus fruticosus), which are known to include a variety of bioactive substances, have been extensively studied for their antioxidant properties. Blackberries possess multiple health beneficial effects, including anti-inflammation, anti-atherosclerosis, anti-tumor and immunomodulatory activity. However, the potential biological effects and precise molecular mechanisms of the fermented extracts remain largely unexplored. In this research, we demonstrate the effect of blackberries fermented with Lactobacillus for addressing obesity. We investigated the effect of blackberries fermented by Lactobacillus on mice fed a high-fat (60% kcal) diet for 12 weeks. Fermented blackberry administration reduced the body weight and epididymal fat caused by a high-fat diet compared to the obese group. The triglyceride and total cholesterol, which are blood lipid indicators, and the levels of leptin, which is an insulin resistance indicator, were significantly increased in the obese group but were significantly decreased in the fermented blackberries-treated group. Additionally, the expression of adipogenesis marker proteins, such as CEBPα, PPAR-γ and SREBP-1, was significantly increased in the obese group, whereas it was decreased in the fermented blackberries-treated group. These results suggest that fermented blackberries have a protective effect against high-fat-diet-induced obesity by inhibiting adipogenesis and are a potential candidate for the treatment of obesity.

ErbB3-binding protein 1(Ebp1) has two isoforms, p42 Ebp1 and p48 Ebp1, both of which can regulate cell growth and differentiation. But these isoforms often have opposite effects, including contradictory roles in regulation of cell growth in different tissues and cells. P48 Ebp1 belongs to the full-length sequence, while conformational changes in the crystal structure of p42 Ebp1 reveals a lack of an α helix at the amino terminus. Due to the differences in the structures of these two isoforms, they have different binding partners and protein modifications. Ebp1 can function as both an oncogene and a tumor suppressor factor. However, the underlying mechanisms by which these two isoforms exert opposite functions are still not fully understood. In this review, we summarize the genes and the structures of protein of these two isoforms, protein modifications, binding partners and the association of different isoforms with diseases.