Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
Department of Computational Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
BMC Med Genomics. 2024 Nov 29;17(1):282. doi: 10.1186/s12920-024-02039-7.
Rare variants in epigenes (a.k.a. chromatin modifiers), a class of genes that control epigenetic regulation, are commonly identified in both pediatric neurodevelopmental syndromes and as somatic variants in cancer. However, little is known about the extent of the shared disruption of signaling pathways by the same epigene across different diseases. To address this, we study an epigene, Additional Sex Combs-like 1 (ASXL1), where truncating heterozygous variants cause Bohring-Opitz syndrome (BOS, OMIM #605039), a germline neurodevelopmental disorder, while somatic variants are driver events in acute myeloid leukemia (AML). No BOS patients have been reported to have AML.
This study explores common pathways dysregulated by ASXL1 variants in patients with BOS and AML. We analyzed whole blood transcriptomic and DNA methylation data from patients with BOS and AML with ASXL1-variant (AML-ASXL1) and examined differential exon usage and cell proportions.
Our analyses identified common molecular signatures between BOS and AML-ASXL1 and highlighted key biomarkers, including VANGL2, GRIK5 and GREM2, that are dysregulated across samples with ASXL1 variants, regardless of disease type. Notably, our data revealed significant de-repression of posterior homeobox A (HOXA) genes and upregulation of Wnt-signaling and hematopoietic regulator HOXB4. While we discovered many shared epigenetic and transcriptomic features, we also identified differential splice isoforms in RUNX3 where the long isoform, p46, is preferentially expressed in BOS, while the shorter p44 isoform is expressed in AML-ASXL1.
Our findings highlight the strong effects of ASXL1 variants that supersede cell-type and even disease states. This is the first direct comparison of transcriptomic and methylation profiles driven by pathogenic variants in a chromatin modifier gene in distinct diseases. Similar to RASopathies, in which pathogenic variants in many genes lead to overlapping phenotypes that can be treated by inhibiting a common pathway, our data identifies common pathways for ASXL1 variants that can be targeted for both disease states. Comparative approaches of high-penetrance genetic variants across cell types and disease states can identify targetable pathways to treat multiple diseases. Finally, our work highlights the connections of epigenes, such as ASXL1, to an underlying stem-cell state in both early development and in malignancy.
表观基因（又称染色质修饰因子）中的罕见变异，是一类控制表观遗传调控的基因，在儿科神经发育综合征和癌症的体细胞变异中都很常见。然而，人们对同一表观基因在不同疾病中通过相同信号通路的破坏程度知之甚少。为了解决这个问题，我们研究了一个表观基因，即额外的性梳样蛋白 1（ASXL1），其中截断杂合变体导致博林-奥皮茨综合征（BOS，OMIM#605039），一种生殖系神经发育障碍，而体细胞变体是急性髓系白血病（AML）的驱动事件。没有 BOS 患者被报道患有 AML。
本研究探讨了 BOS 和 AML 患者中 ASXL1 变异体失调的共同途径。我们分析了 ASXL1 变异（AML-ASXL1）的 BOS 和 AML 患者的全血转录组和 DNA 甲基化数据，并检查了差异外显子使用和细胞比例。
我们的分析在 BOS 和 AML-ASXL1 之间确定了共同的分子特征，并强调了关键的生物标志物，包括 VANGL2、GRIK5 和 GREM2，这些标志物在 ASXL1 变异体的样本中失调，无论疾病类型如何。值得注意的是，我们的数据显示，HOXA 基因的后体 homeobox A（HOXA）基因显著去抑制，Wnt 信号和造血调节因子 HOXB4 上调。虽然我们发现了许多共同的表观遗传和转录组特征，但我们也在 RUNX3 中发现了不同的剪接异构体，其中长异构体 p46 优先在 BOS 中表达，而短异构体 p44 则在 AML-ASXL1 中表达。
我们的研究结果强调了 ASXL1 变异的强大影响，这种影响超越了细胞类型甚至疾病状态。这是首次直接比较染色质修饰基因中致病性变异在不同疾病中的转录组和甲基化谱。类似于 RAS 病，其中许多基因的致病性变异导致重叠的表型，可以通过抑制共同的通路来治疗，我们的数据确定了 ASXL1 变异的共同途径，可以针对两种疾病状态进行靶向治疗。通过对细胞类型和疾病状态的高外显率遗传变异进行比较性研究，可以确定可治疗多种疾病的靶向途径。最后，我们的工作强调了表观基因（如 ASXL1）与早期发育和恶性肿瘤中潜在干细胞状态的联系。
