Cortese Rene, Zhang Chunling, Bao Riyue, Andrade Jorge, Khalyfa Abdelnaby, Mokhlesi Babak, Gozal David
Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL.
Center for Research Informatics, University of Chicago, Chicago, IL.
Chest. 2016 Jul;150(1):91-101. doi: 10.1016/j.chest.2016.02.648. Epub 2016 Feb 26.
OSA is a highly prevalent condition that is associated with a wide range of long-term morbidities including metabolic, cardiovascular, and cognitive alterations, possibly via activation of systemic inflammatory and oxidative stress pathways. Implementation of positive airway pressure (PAP) is the first-line treatment for OSA, as well as for obesity hypoventilation syndrome (OHS), its most severe phenotype. However, the molecular and cellular mechanisms underlying OHS-induced morbidities and their response to PAP treatment remain unclear, and could be mediated, in part, by OSA-induced epigenetic changes.
Blood was collected before starting PAP treatment (PRE group), as well as 6 weeks after PAP treatment (POST group) in 15 adult patients with OHS. DNA methylation profiles were studied by methylated DNA immunoprecipitation coupled to microarrays (MeDIP-chip) in six representative patients and further verified in a cohort of 15 patients by MeDIP-quantitative PCR.
We identified 1,847 regions showing significant differential DNA methylation (P < .001; model-based analysis of tiling arrays score, > 4) between the groups. Analysis of biochemical pathways and gene networks demonstrated that differentially methylated regions were associated with immune responses, and particularly with mechanisms governing gene regulation by peroxisome proliferation-activated receptors (PPARs). Single-locus quantitative PCR analysis revealed that DNA methylation was increased at the PPAR-responsive elements (PPAREs) of eight genes in the post-treatment samples (PRE/POST fold changes: ABCA1, 3.11; ABCG1, 1.72; CD36, 5.04; FABP4, 2.49; HMOX, 2.74; NOS2, 7.78; PEPCK, 9.27; and ADIPOQ, 1.73), suggesting that PAP treatment leads to an increase in DNA methylation at PPAREs, possibly affecting the binding of the PPAR-γ complex and downstream gene expression.
Our work provides initial evidence of epigenetic regulation particularly involving metabolic pathways in patients with OHS who are responsive to PAP treatment.
阻塞性睡眠呼吸暂停（OSA）是一种高度流行的疾病，与多种长期发病情况相关，包括代谢、心血管和认知改变，可能是通过激活全身炎症和氧化应激途径。实施气道正压通气（PAP）是OSA以及其最严重的表型——肥胖低通气综合征（OHS）的一线治疗方法。然而，OHS诱发发病的分子和细胞机制以及它们对PAP治疗的反应仍不清楚，并且可能部分由OSA诱发的表观遗传变化介导。
收集15例成年OHS患者开始PAP治疗前（PRE组）以及PAP治疗6周后（POST组）的血液。通过甲基化DNA免疫沉淀结合微阵列（MeDIP芯片）研究6例代表性患者的DNA甲基化谱，并通过MeDIP定量PCR在15例患者队列中进一步验证。
我们鉴定出1847个区域在两组之间显示出显著的DNA甲基化差异（P <.001；基于模型的平铺阵列分析得分，> 4）。对生化途径和基因网络的分析表明，差异甲基化区域与免疫反应相关，特别是与过氧化物酶体增殖激活受体（PPARs）调控基因表达的机制相关。单基因座定量PCR分析显示，治疗后样本中8个基因的PPAR反应元件（PPAREs）处的DNA甲基化增加（PRE/POST倍数变化：ABCA1，3.11；ABCG1，1.72；CD36，5.04；FABP4，2.49；HMOX，2.74；NOS2，7.78；PEPCK，9.27；和ADIPOQ，1.73），表明PAP治疗导致PPAREs处的DNA甲基化增加，可能影响PPAR-γ复合物的结合和下游基因表达。
我们的工作提供了表观遗传调控的初步证据，特别是涉及对PAP治疗有反应的OHS患者的代谢途径。
