Disease specific epigenetic deregulation of enhancers, transposons and polycomb targets in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), characterized by a fusion between the PML and RARA genes and by a block in the myeloid maturation at the promyelocytic stage. This study investigates the epigenetic landscape of APL by integrating ChIP-seq data on eight histone modifications and RNA-seq in APL as well as non-APL AML. APL showed a distinct chromatin profile that differed from non-APL AML. We describe APL specific changes in H3K27ac, H3K9me3 and H3K27me3 with impact on enhancer activity, repression of transposable elements and Polycomb regulated gene repression. The APL-specific H3K27ac pattern identifies APL-specific enhancer and super-enhancer regions, including a subset of enhancers that are bound by the PML-RARA fusion protein. While chromatin bound specifically by PML-RARA were dominantly active, APL was also characterized by gain of APL-specific heterochromatin states with significant gains of H3K9me3 enriched lamina-associated domains and the transposable elements LINE, LTR and SINE. These findings suggest a unique enhancer and heterochromatin profile in APL, with implications for transcription regulation and treatment response. These findings offer novel insights into the pathogenesis of APL. There was 1 experimental group (ATRA for 72hr) and one untreated control. The experimental group and control were analyzed in triplicate.

急性早幼粒细胞白血病（Acute promyelocytic leukemia, APL）是急性髓系白血病（acute myeloid leukemia, AML）的一个亚型，其特征为PML基因与RARA基因发生融合，且髓系成熟过程阻滞于早幼粒细胞阶段。本研究通过整合APL与非APL型AML的8种组蛋白修饰（histone modifications）的染色质免疫共沉淀测序（ChIP-seq）数据及RNA测序（RNA-seq）数据，解析了APL的表观遗传图谱（epigenetic landscape）。研究发现，APL呈现出与非APL型AML截然不同的独特染色质特征。本研究描述了APL特异性的H3K27ac、H3K9me3及H3K27me3水平变化，这些变化可影响增强子活性、转座元件（transposable elements）的沉默以及多梳蛋白（Polycomb）调控的基因抑制过程。APL特异性的H3K27ac图谱可识别APL特异性增强子及超级增强子区域，其中包含一类被PML-RARA融合蛋白结合的增强子亚群。尽管PML-RARA特异性结合的染色质多处于活跃状态，但APL同时还具有APL特异性异染色质（heterochromatin）状态获得的特征：表现为H3K9me3富集的核纤层关联结构域（lamina-associated domains）以及转座元件LINE、LTR与SINE的显著富集。上述研究结果表明，APL具有独特的增强子与异染色质特征，这对转录调控及治疗响应具有潜在意义，同时为APL的发病机制提供了全新的见解。本研究设置了1个实验组（全反式维甲酸（ATRA, all-trans retinoic acid）处理72小时）与1个未处理对照组，实验组与对照组均进行了三次生物学重复。