Jąkalski Marcin, Bruhn-Olszewska Bożena, Rychlicka-Buniowska Edyta, Davies Hanna, Sarkisyan Daniil, Siedlar Maciej, Baran Jarosław, Węglarczyk Kazimierz, Jaszczynski Janusz, Ryś Janusz, Gedraitis Vilmantas, Filipowicz Natalia, Klich-Rączka Alicja, Kilander Lena, Ingelsson Martin, Dumanski Jan P
3P-Medicine Laboratory, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland.
Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Cell Mol Life Sci. 2025 Feb 25;82(1):93. doi: 10.1007/s00018-025-05618-8.
Alzheimer's disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of chromosome Y (LOY) in leukocytes is strongly associated with AD. We studied here DNA methylation and RNA expression in sorted monocytes and granulocytes with and without LOY from male AD patients. Through multi-omic analysis, we identified new candidate genes along with those previously associated with AD. Global analyses of DNA methylation in samples with LOY vs. normal state showed that hypomethylation dominated both in granulocytes and monocytes. Our findings highlight LOY-related differences in DNA methylation that occur in gene regulatory regions. Specifically, we observed alterations in key genes involved in leukocyte differentiation: FLI1, involved in early hematopoiesis; RUNX1, essential for blood cell development; RARA, regulating gene expression in response to retinoic acid; CANX, crucial for protein folding; CEBPB, a transcription factor important for immune responses; and MYADM, implicated in cell adhesion and migration. Moreover, protein-protein interaction analysis in granulocytes identified that products of two of these genes, CANX and CEBPB, are key hub proteins. This research underscores the potential of multi-omic approach in pure hematopoietic cell populations to uncover the molecular underpinnings of AD. Finally, our results link previous analysis showing impact of LOY on leukocyte differentiation, LOY-associated transcriptional dysregulation and GWAS studies of LOY.
由于人类寿命的延长，阿尔茨海默病（AD）成为一个日益普遍的社会问题。在男性中，白细胞中Y染色体缺失（LOY）与AD密切相关。我们在此研究了来自男性AD患者的、具有和不具有LOY的分选单核细胞和粒细胞中的DNA甲基化和RNA表达情况。通过多组学分析，我们确定了新的候选基因以及先前与AD相关的基因。对具有LOY的样本与正常状态样本进行的全基因组DNA甲基化分析表明，低甲基化在粒细胞和单核细胞中均占主导地位。我们的研究结果突出了在基因调控区域发生的与LOY相关的DNA甲基化差异。具体而言，我们观察到参与白细胞分化的关键基因发生了改变：FLI1参与早期造血过程；RUNX1对血细胞发育至关重要；RARA响应视黄酸调节基因表达；CANX对蛋白质折叠至关重要；CEBPB是免疫反应中重要的转录因子；MYADM与细胞黏附和迁移有关。此外，粒细胞中的蛋白质-蛋白质相互作用分析确定，这些基因中的两个基因CANX和CEBPB的产物是关键枢纽蛋白。这项研究强调了多组学方法在纯造血细胞群体中揭示AD分子基础的潜力。最后，我们的结果将先前显示LOY对白细胞分化影响的分析、与LOY相关的转录失调以及LOY的全基因组关联研究联系起来。
