Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome.
Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome.
复制标题
DOI：
10.1126/sciadv.abf7346
复制
发表时间：
2021-05
期刊：
影响因子：
13.6
通讯作者：
Kim TK
中科院分区：
文献类型：
--
作者：
Kim SK;Liu X;Park J;Um D;Kilaru G;Chiang CM;Kang M;Huber KM;Kang K;Kim TK
BET家族蛋白的协调是记忆行为和FXS的基因调控网络的特征。溴结构域和末端外蛋白（BET）是表观遗传学的读者，在基因调控中发挥关键作用。存在于所有BET家族成员中的溴结构域的药理学抑制是用于各种疾病的有希望的治疗策略，但其对个体家族成员的影响尚未得到很好的理解。使用神经元中的转录诱导范例，我们已经系统地证明了三种主要的BET家族蛋白（BRD 2/3/4）参与转录，具有不同的募集动力学、相互依赖性和对溴结构域抑制剂JQ 1的敏感性。在脆性X综合征（FXS）的小鼠模型中，BRD 2/3和BRD 4表现出相反的表达和染色质结合改变，与转录失调相关。CBP/p300组蛋白乙酰转移酶（HAT）活性的急性抑制恢复了BRD 2和BRD 4的改变的结合模式，并挽救了FXS中的记忆障碍。我们的研究强调了理解BET配位的重要性，BET配位由具有不同底物特异性的HAT之间的平衡作用控制。
The coordination of BET family proteins is a feature of the gene regulatory network underlying memory behavior and FXS. Bromodomain and extraterminal proteins (BET) are epigenetic readers that play critical roles in gene regulation. Pharmacologic inhibition of the bromodomain present in all BET family members is a promising therapeutic strategy for various diseases, but its impact on individual family members has not been well understood. Using a transcriptional induction paradigm in neurons, we have systematically demonstrated that three major BET family proteins (BRD2/3/4) participated in transcription with different recruitment kinetics, interdependency, and sensitivity to a bromodomain inhibitor, JQ1. In a mouse model of fragile X syndrome (FXS), BRD2/3 and BRD4 showed oppositely altered expression and chromatin binding, correlating with transcriptional dysregulation. Acute inhibition of CBP/p300 histone acetyltransferase (HAT) activity restored the altered binding patterns of BRD2 and BRD4 and rescued memory impairment in FXS. Our study emphasizes the importance of understanding the BET coordination controlled by a balanced action between HATs with different substrate specificity.
登录
查看更多内容
影响因子：
5.8
作者：
Barnett, Derek W.;Garrison, Erik K.;Marth, Gabor T.
通讯作者：
Marth, Gabor T.
影响因子：
16
作者：
Hsu SC;Gilgenast TG;Bartman CR;Edwards CR;Stonestrom AJ;Huang P;Emerson DJ;Evans P;Werner MT;Keller CA;Giardine B;Hardison RC;Raj A;Phillips-Cremins JE;Blobel GA
通讯作者：
Blobel GA
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
10.5
作者：
Alekseyenko AA;Walsh EM;Wang X;Grayson AR;Hsi PT;Kharchenko PV;Kuroda MI;French CA
通讯作者：
French CA
影响因子：
64.5
作者：
Anand P;Brown JD;Lin CY;Qi J;Zhang R;Artero PC;Alaiti MA;Bullard J;Alazem K;Margulies KB;Cappola TP;Lemieux M;Plutzky J;Bradner JE;Haldar SM
通讯作者：
Haldar SM