PO.PS01.03 · 人群科学

慢性淋巴细胞白血病中与祖先相关的表观遗传学差异

Ancestry-associated epigenetic differences in chronic lymphocytic leukemia

编号 5064 展板 4 时间 4/21 09:00–12:00 区域 Section 36 主讲 Zhiquan Wang, PhD

分会场 Etiology and Molecular Epidemiology Approaches to Decipher Cancer Disparities

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作者与单位 Authors & Affiliations

Zhiquan Wang¹, Huihuang Yan¹, Mingma Sherpa¹, Daniel Bihnam², Cristine Allmer¹, Chantal McCabe¹, Daniel O’Brien¹, Dennis P. Robinson¹, James R. Cerhan³, Neil E. Kay¹, Sameer A. Parikh¹, Esteban Braggio⁴, Susan Slager¹

¹Mayo Clinic, Rochester, MN,²Mayo Clinic, Phoenix, AZ,³Mayo Clinic College of Medicine and Science, Rochester, MN,⁴Mayo Clinic Arizona, Scottsdale, AZ

摘要 Abstract

中文摘要

背景：CLL的发病率因祖先而异，欧洲血统（EA）个体的发病率高于非洲血统（AA）个体。表观遗传变异对这些差异的贡献仍不清楚。我们研究了EA和AA的CLL患者的染色质可及性、组蛋白修饰和基因表达，以识别与祖先相关的表观遗传学特征。方法：对15名AA和51名EA患者的血液克隆性B细胞进行了ATAC-seq；对8例AA和12例EA病例进行了六种组蛋白标记（H3K4me1、H3K4me3、H3K27ac、H3K9me3、H3K27me3、H3K36me3）的CUT&Tag分析；对所有样本进行了RNA-seq。祖先经遗传学确认。差异区域使用ENCODE和Hi-C数据集与基因关联。结果：ATAC-seq显示，与EA相比，AA中有4,955个区域可及性增加，3,000个区域可及性降低（倍数变化>2，FDR≤0.05）。可及性增加的区域映射到2,313个基因；其中599个上调，并富集于TNF-alpha/NF-κB（p=1.40E-53）和凋亡通路（p=6.90E-11）。可及性降低的区域关联到1,953个基因；其中317个下调，富集于干扰素-gamma应答（p=1.04E-03）和IL-6/JAK/STAT3信号通路（p=6.41E-03）。组蛋白分析显示所有标记均存在祖先特异性变化。对于H3K27ac（活性增强子），AA中信号降低的68个基因下调，并富集于干扰素-gamma（p=1.55E-06）和IL-6/JAK/STAT3（p=9.62E-05）通路。AA中H3K27me3（抑制性组蛋白修饰）增加影响了399个基因，富集于IL-6/JAK/STAT3（p=8.13E-09）和干扰素-gamma（p=2.48E-05）通路。这些发现提示活性和抑制性染色质状态之间存在协调调控。结论：尽管样本量有限，本研究提示AA和EA祖先之间在CLL的表观遗传学特征上可能存在差异，将染色质可及性和组蛋白修饰与肿瘤生物学相关通路联系起来。这些特征也可能促成CLL发病率因祖先而异的差异。未来需要更多患者的研究和功能验证实验，以阐明这些表观遗传学差异在CLL发病机制中的作用。

查看英文原文 English abstract

Background: CLL incidence differs by ancestry, with higher rates in individuals of European ancestry (EA) than African ancestry (AA). The contribution of epigenetic variation to these disparities remains unclear. We investigated chromatin accessibility, histone modifications, and gene expression in CLL patients of EA and AA to identify ancestry-associated epigenetic signatures. Methods: ATAC-seq was performed on blood clonal B cells from 15 AA and 51 EA patients; CUT&Tag profiling of six histone marks (H3K4me1, H3K4me3, H3K27ac, H3K9me3, H3K27me3, H3K36me3) was done in 8 AA and 12 EA cases; RNA-seq was generated for all samples. Ancestry was genetically confirmed. Differential regions were linked to genes using ENCODE and Hi-C datasets. Results: ATAC-seq revealed 4,955 regions with increased and 3,000 with decreased accessibility in AA vs EA (fold change >2, FDR ≤0.05). Regions with increased accessibility mapped to 2,313 genes; 599 were upregulated and enriched in TNF-alpha/NF-κB (p=1.40E-53) and apoptosis pathways (p=6.90E-11). Regions with decreased accessibility linked to 1,953 genes; 317 were downregulated, enriched in interferon-gamma response (p=1.04E-03) and IL-6/JAK/STAT3 signaling (p=6.41E-03). Histone profiling showed ancestry-specific changes across all marks. For H3K27ac (active enhancer), 68 genes with a decreased signal in AA were downregulated and enriched in interferon-gamma (p=1.55E-06) and IL-6/JAK/STAT3 (p=9.62E-05) pathways. Increased H3K27me3 (repressive histone modification) in AA affected 399 genes enriched in IL-6/JAK/STAT3 (p=8.13E-09) and interferon-gamma (p=2.48E-05) pathways. These findings suggest coordinated regulation by active and repressive chromatin states. Conclusions: Despite limited sample size, this study suggests differences between AA and EA ancestries may exist in epigenetic signatures in CLL, implicating chromatin accessibility and histone modifications in pathways relevant to tumor biology. These signatures may also contribute to the differences in CLL incidence by ancestry. Future studies with more patients and functional validation experiments are needed to clarify the role of these epigenetic differences in CLL pathogenesis.

利益披露 Disclosure

Z. Wang, None.. M. Sherpa, None.. D. Bihnam, None.

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