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<p>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: <i>FLI1</i>, involved in early hematopoiesis; <i>RUNX1</i>, essential for blood cell development; <i>RARA</i>, regulating gene expression in response to retinoic acid; <i>CANX</i>, crucial for protein folding; <i>CEBPB</i>, a transcription factor important for immune responses; and <i>MYADM</i>, implicated in cell adhesion and migration. Moreover, protein–protein interaction analysis in granulocytes identified that products of two of these genes, <i>CANX</i> and <i>CEBPB</i>, 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.</p>

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DNA methylation patterns contribute to changes of cellular differentiation pathways in leukocytes with LOY from patients with Alzheimer´s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月25日

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  • Marcin Jąkalski,
  • Bożena Bruhn-Olszewska,
  • Edyta Rychlicka-Buniowska,
  • Hanna Davies,
  • Daniil Sarkisyan,
  • Maciej Siedlar,
  • Jarosław Baran,
  • Kazimierz Węglarczyk,
  • Janusz Jaszczynski,
  • Janusz Ryś,
  • Vilmantas Gedraitis,
  • Natalia Filipowicz,
  • Alicja Klich-Rączka,
  • Lena Kilander,
  • Martin Ingelsson,
  • Jan P. Dumanski

摘要

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.