Transcriptome Analysis Revealed Impaired cAMP Responsiveness in PHF21A-Deficient Human Cells.
Transcriptome Analysis Revealed Impaired cAMP Responsiveness in PHF21A-Deficient Human Cells.
复制标题
DOI：
10.1016/j.neuroscience.2017.05.031
复制
发表时间：
2018-02-01
期刊：
影响因子：
3.3
通讯作者：
Iwase S
中科院分区：
文献类型：
--
作者：
Porter RS;Murata-Nakamura Y;Nagasu H;Kim HG;Iwase S
Potocki-Shaffer综合征是一种罕见的与11p11.2染色体微缺失相关的神经发育综合征。遗传证据表明，PHF21A（一种编码组蛋白结合蛋白的基因）的单倍不足可能导致Potocki-Shaffer综合征的智力残疾和颅面异常。然而，先前的工作尚未研究PHF21A表达降低的分子后果。在这项研究中，我们通过rna测序（RNA-Seq）分析了与未受影响的个体相比，PHF21A杂合缺失的两种患者来源的细胞系，并鉴定出1885个常见的错误调控基因。患者细胞表现出与学习和记忆相关的关键通路下调，包括camp信号通路基因。我们发现PHF21A是在cAMP类似物forskolin刺激后完全诱导携带cAMP响应元件（CRE）的荧光素酶报告蛋白所必需的。最后，phf21a缺陷的患者来源的细胞在福斯克林刺激后表现出直接早期基因的延迟诱导。这些结果表明，对camp信号的反应受损可能参与了PHF21A缺乏的病理过程。
Potocki-Shaffer Syndrome is a rare neurodevelopmental syndrome associated with microdeletion of a region of Chromosome 11p11.2. Genetic evidence has implicated haploinsufficiency of PHF21A, a gene that encodes a histone-binding protein, as the likely cause of intellectual disability and craniofacial abnormalities in Potocki-Shaffer Syndrome. Previous work, however, has not investigated the molecular consequences of reduced PHF21A expression. In this study, we analyzed by RNA-Sequencing (RNA-Seq) two patient-derived cell lines with heterozygous loss of PHF21A compared to unaffected individuals and identified 1,885 genes that were commonly misregulated. The patient cells displayed down-regulation of key pathways relevant to learning and memory, including cAMP-signaling pathway genes. We found that PHF21A is required for full induction of a luciferase reporter carrying cAMP-responsive elements (CRE) following stimulation by the cAMP analog, forskolin. Finally, PHF21A-deficient patient-derived cells exhibited a delayed induction of immediate early genes following forskolin stimulation. These results suggest that an impaired response to cAMP-signaling might be involved in the pathology of PHF21A deficiency.
登录
查看更多内容
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
30.8
作者：
Mavrogiannis, LA;Antonopoulou, I;Wilkie, AOM
通讯作者：
Wilkie, AOM
影响因子：
64.5
作者：
BOURTCHULADZE, R;FRENGUELLI, B;SILVA, AJ
通讯作者：
SILVA, AJ
DOI：
10.1073/pnas.0401827101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Bruce, AW;Donaldson, IJ;Buckley, NJ
通讯作者：
Buckley, NJ
影响因子：
4.5
作者：
Chahrour MH;Yu TW;Lim ET;Ataman B;Coulter ME;Hill RS;Stevens CR;Schubert CR;ARRA Autism Sequencing Collaboration;Greenberg ME;Gabriel SB;Walsh CA
通讯作者：
Walsh CA