A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance.
A small-molecule screen reveals novel modulators of MeCP2 and X-chromosome inactivation maintenance.
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DOI：
10.1186/s11689-020-09332-3
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发表时间：
2020-11-10
影响因子：
4.9
通讯作者：
Cerase A
中科院分区：
文献类型：
--
作者：
Lee HM;Kuijer MB;Ruiz Blanes N;Clark EP;Aita M;Galiano Arjona L;Kokot A;Sciaky N;Simon JM;Bhatnagar S;Philpot BD;Cerase A
Rett综合征(RTT)是一种由X-连锁甲基CpG结合蛋白2(MeCP2)基因突变引起的神经发育障碍。虽然MeCP2突变在大多数男性中是致命的，但女性在出生后存活下来，但表现出严重的神经缺陷。由于X染色体失活(XCI)是一个随机过程，大约50%的细胞会沉默MeCP2基因的野生型(WT)拷贝。因此，重新激活沉默的MeCP2的WT拷贝可以为RTT提供治疗干预。为了实现这一目标，我们使用MeCP2-荧光素酶报告细胞系和MeCP2-EGFP小鼠模型的皮质神经元，从几个文库中筛选出约28,000个小分子化合物。我们使用发光或荧光的增益/增加作为MeCP2重新激活的读数，并测试这些药物在不同药物方案、条件和细胞环境下的疗效。通过体外和体外实验，我们确定JAK/STAT途径的抑制剂是XCI再活化剂。特别是，我们发现，在不同的细胞环境中，Janus Kinase 2(JAK2)激酶抑制剂AG-490和PAN JAK/STAT抑制剂Jaki能够重新激活非活性X染色体上的MeCP2。我们的结果表明，抑制JAK/STAT通路是恢复MeCP2基因表达的一条新的潜在途径，作为一种有效的RTT治疗。网上版载有补充材料，可在10.1186/s11689020-09332-3查阅。
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MeCP2) gene. While MeCP2 mutations are lethal in most males, females survive birth but show severe neurological defects. Because X-chromosome inactivation (XCI) is a random process, approximately 50% of the cells silence the wild-type (WT) copy of the MeCP2 gene. Thus, reactivating the silent WT copy of MeCP2 could provide therapeutic intervention for RTT. Toward this goal, we screened ~ 28,000 small-molecule compounds from several libraries using a MeCP2-luciferase reporter cell line and cortical neurons from a MeCP2-EGFP mouse model. We used gain/increase of luminescence or fluorescence as a readout of MeCP2 reactivation and tested the efficacy of these drugs under different drug regimens, conditions, and cellular contexts. We identified inhibitors of the JAK/STAT pathway as XCI-reactivating agents, both by in vitro and ex vivo assays. In particular, we show that AG-490, a Janus Kinase 2 (JAK2) kinase inhibitor, and Jaki, a pan JAK/STAT inhibitor, are capable of reactivating MeCP2 from the inactive X chromosome, in different cellular contexts. Our results suggest that inhibition of the JAK/STAT pathway is a new potential pathway to reinstate MeCP2 gene expression as an efficient RTT treatment. The online version contains supplementary material available at 10.1186/s11689-020-09332-3.
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DOI：
10.1126/science.aal2512
发表时间：
2017-06-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Almeida M;Pintacuda G;Masui O;Koseki Y;Gdula M;Cerase A;Brown D;Mould A;Innocent C;Nakayama M;Schermelleh L;Nesterova TB;Koseki H;Brockdorff N
通讯作者：
Brockdorff N
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.8
作者：
Huang, Hsien-Sung;Allen, John A.;Mabb, Angela M.;King, Ian F.;Miriyala, Jayalakshmi;Taylor-Blake, Bonnie;Sciaky, Noah;Dutton, J. Walter, Jr.;Lee, Hyeong-Min;Chen, Xin;Jin, Jian;Bridges, Arlene S.;Zylka, Mark J.;Roth, Bryan L.;Philpot, Benjamin D.
通讯作者：
Philpot, Benjamin D.
DOI：
10.1073/pnas.1617597113
发表时间：
2016-12-13
影响因子：
11.1
作者：
Lessing, Derek;Dial, Thomas O.;Lee, Jeannie T.
通讯作者：
Lee, Jeannie T.
影响因子：
25
作者：
Lyst, Matthew J.;Ekiert, Robert;Ebert, Daniel H.;Merusi, Cara;Nowak, Jakub;Selfridge, Jim;Guy, Jacky;Kastan, Nathaniel R.;Robinson, Nathaniel D.;Alves, Flavia de Lima;Rappsilber, Juri;Greenberg, Michael E.;Bird, Adrian
通讯作者：
Bird, Adrian