Farhangdoost Nargess, Liao Calwing, Liu Yumin, Rochefort Daniel, Aboasali Farah, Pietrantonio Alessia, Alda Martin, Dion Patrick A, Chaumette Boris, Khayachi Anouar, Rouleau Guy A
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Montreal Neurological Institute-Hospital, Montreal, QC, Canada.
Mol Psychiatry. 2025 May 2. doi: 10.1038/s41380-025-03040-x.
The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons. This study uses genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygous AKAP11 LoF mutations on the gene expression landscape and profile the DNA methylation and histone acetylation modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes mainly involved in DNA-binding transcription factor activity, actin binding and cytoskeleton regulation, and cytokine receptor binding. We also show significant downregulation of pathways related to ribosome structure and function, a pathway also altered in BD and SCZ post-mortem brain tissues and heterozygous Akap11-KO mice synapse proteomics. A better understanding of the dysregulations resulting from haploinsufficiency in AKAP11 improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.
基因A激酶锚定蛋白11（AKAP11）最近成为双相情感障碍和精神分裂症之间的一个共同风险因素，由功能丧失（LoF）大效应变体驱动。最近的研究揭示了Akap11突变小鼠模型的神经生理学特征和突触蛋白质组学概况。考虑到AKAP11在结合环磷酸腺苷依赖性蛋白激酶A（PKA）和介导众多底物（如转录因子和表观遗传调节因子）磷酸化方面的作用，并且鉴于染色质改变与双相情感障碍和精神分裂症患者的大脑有关，揭示AKAP11杂合敲除后的转录组和染色质失调至关重要，尤其是在人类神经元中。本研究使用全基因组方法来研究人类诱导多能干细胞（iPSC）衍生神经元中的此类异常。我们展示了杂合AKAP11 LoF突变对基因表达景观的影响，并描绘了DNA甲基化和组蛋白乙酰化修饰。我们总共强调了基因间和内含子增强子异常活性的参与，这些增强子分别富含已知的PBX同源框2（PBX2）和核因子1（NF1）结合基序，参与主要涉及DNA结合转录因子活性、肌动蛋白结合和细胞骨架调节以及细胞因子受体结合的基因的转录失调。我们还显示与核糖体结构和功能相关的通路显著下调，该通路在双相情感障碍和精神分裂症的死后脑组织以及杂合Akap11基因敲除小鼠的突触蛋白质组学中也发生了改变。更好地理解AKAP11单倍体不足导致的失调，有助于我们了解双相情感障碍和精神分裂症的生物学根源和病理生理学，为更好的治疗方法铺平道路。
