Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome.
Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome.
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在Kabuki综合征小鼠模型中，抑制KDM1A活性可恢复成年神经发生并改善海马记忆
DOI：
10.1016/j.omtm.2021.02.011
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发表时间：
2021-03-12
期刊：
影响因子：
--
通讯作者：
Bjornsson HT
中科院分区：
文献类型：
--
作者：
Zhang L;Pilarowski G;Pich EM;Nakatani A;Dunlop J;Baba R;Matsuda S;Daini M;Hattori Y;Matsumoto S;Ito M;Kimura H;Bjornsson HT
歌舞伎综合征(KS)是一种罕见的智力残疾原因，主要由赖氨酸特异性甲基转移酶2D(KMT2D)功能丧失突变引起，KMT2D通常在组蛋白3上的赖氨酸4上添加甲基标记。先前的研究表明，KS(Kmt2d+/βGeo)小鼠模型显示成年神经发生和海马区记忆中断。原则验证研究表明，促进染色质开放的治疗可在出生后挽救神经功能障碍；然而，这些策略是非特异性的，并不直接解决组蛋白甲基化的主要缺陷。由于赖氨酸特异的脱甲基酶1A(LSD1/KDM1A)通常会去除KMT2D添加的H3K4甲基标记，我们推测抑制KDM1A脱甲基酶的活性可能会改善KMT2D缺失引起的分子和表型缺陷。为了验证这一假设，我们评估了最近开发的KDM1a抑制剂(TAK-418)在Kmt2d+/βGeo小鼠中的作用。我们发现，口服TAK-418以剂量依赖的方式增加新生的双皮质激素(DCX)+细胞的数量和海马区的突起。我们还通过蛋白质印迹和染色质免疫沉淀测序(CHIP-SEQ)观察了TAK-418对海马组蛋白修饰缺陷的修复作用。治疗挽救了基因表达异常，包括即刻早期基因的表达异常，如FBJ骨肉瘤癌基因(Fos)和FBJ骨肉瘤癌基因同源B(FosB)。Tak418治疗2周后，Kmt2d+/βGeo小鼠表现出海马区记忆缺陷的正常化。综上所述，我们的数据表明，抑制KDM1A是一种可行的治疗KS的策略，并支持KMT2D功能障碍继发的表观遗传失调在KS出生后神经疾病表型中起主要作用的假设。KMT2D和KDM1A对组蛋白3赖氨酸4甲基化有相反的作用。在这项研究中，我们证明了KDM1A的抑制剂TAK-418可以挽救Kmt2d突变的歌舞伎综合征小鼠模型中异常的基因表达和染色质水平，以及成年神经发生和海马体记忆的缺陷。
Kabuki syndrome (KS) is a rare cause of intellectual disability primarily caused by loss-of-function mutations in lysine-specific methyltransferase 2D (KMT2D), which normally adds methyl marks to lysine 4 on histone 3. Previous studies have shown that a mouse model of KS (Kmt2d+/βGeo) demonstrates disruption of adult neurogenesis and hippocampal memory. Proof-of-principle studies have shown postnatal rescue of neurological dysfunction following treatments that promote chromatin opening; however, these strategies are non-specific and do not directly address the primary defect of histone methylation. Since lysine-specific demethylase 1A (LSD1/KDM1A) normally removes the H3K4 methyl marks added by KMT2D, we hypothesized that inhibition of KDM1A demethylase activity may ameliorate molecular and phenotypic defects stemming from KMT2D loss. To test this hypothesis, we evaluated a recently developed KDM1A inhibitor (TAK-418) in Kmt2d+/βGeo mice. We found that orally administered TAK-418 increases the numbers of newly born doublecortin (DCX)+ cells and processes in the hippocampus in a dose-dependent manner. We also observed TAK-418-dependent rescue of histone modification defects in hippocampus both by western blot and chromatin immunoprecipitation sequencing (ChIP-seq). Treatment rescues gene expression abnormalities including those of immediate early genes such as FBJ osteosarcoma oncogene (Fos) and FBJ osteosarcoma oncogene homolog B (Fosb). After 2 weeks of TAK-418, Kmt2d+/βGeo mice demonstrated normalization of hippocampal memory defects. In summary, our data suggest that KDM1A inhibition is a plausible treatment strategy for KS and support the hypothesis that the epigenetic dysregulation secondary to KMT2D dysfunction plays a major role in the postnatal neurological disease phenotype in KS. KMT2D and KDM1A have opposing effects on histone 3 lysine 4 methylation. In this study, we show that TAK-418, an inhibitor of KDM1A, rescues abnormal gene expression and chromatin levels as well as defects of adult neurogenesis and hippocampal memory in a mouse model of Kabuki syndrome carrying a mutation in Kmt2d.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
13.6
作者：
Cao K;Collings CK;Morgan MA;Marshall SA;Rendleman EJ;Ozark PA;Smith ER;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
7
作者：
Bjornsson HT
通讯作者：
Bjornsson HT
影响因子：
64.8
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
通讯作者：
Helin, Kristian