Evidence of shared transcriptomic dysregulation of HNRNPU-related disorder between human organoids and embryonic mice.
Evidence of shared transcriptomic dysregulation of HNRNPU-related disorder between human organoids and embryonic mice.
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DOI：
10.1016/j.isci.2022.105797
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发表时间：
2023-01-20
期刊：
影响因子：
5.8
通讯作者：
Goldstein, David B.
中科院分区：
文献类型：
--
作者：
Ressler, Andrew K.;Sampaio, Gabriela L. A.;Dugger, Sarah A.;Sapir, Tamar;Krizay, Daniel;Boland, Michael J.;Reiner, Orly;Goldstein, David B.
为神经发育障碍创造有效的治疗方法仍然难以捉摸。一种新的治疗神经发育障碍的药物发现方法是在适当的模型系统中表征转录组范围的异常，并基于其恢复功能相关表达模式的能力来筛选治疗方法。我们在HNRNPU相关疾病的人类模型中表征了转录调控障碍，以探索这种范式的潜力。我们确定了功能相关途径中广泛存在的调节失调，然后将人类模型中的调节失调与胚胎和围产期小鼠的转录差异进行比较，以确定体外人类模型中的调节失调是否在HNRNPU相关疾病的体内模型中部分复制。引人注目的是，我们发现45天大的人类器官和来自不同HNRNPU相关疾病模型的胚胎小鼠之间的协同失调丰富，但不是围产期小鼠。因此，hnRNPU缺乏的人类类器官可能只适合于在特定的发育时间窗口内模拟某些细胞类型的转录失调。HNRNPU+/−HCOs明显小于野生型有机物HNRNPU+/−HCOs显示前体种群中异常基因的数量增加HNRNPU+/−HCOs与胚胎和围产期HnrnPU突变的HNRNPU+/HnrnPU突变体皮质转录失调一致的小鼠胚胎和围产期HnrnPU突变体皮质没有表现出一致的失调精神病学；生物科学；发育生物学；胚胎学；Omics；转录组学
Generating effective therapies for neurodevelopmental disorders has remained elusive. An emerging drug discovery approach for neurodevelopmental disorders is to characterize transcriptome-wide dysregulation in an appropriate model system and screen therapeutics based on their capacity to restore functionally relevant expression patterns. We characterized transcriptomic dysregulation in a human model of HNRNPU-related disorder to explore the potential of such a paradigm. We identified widespread dysregulation in functionally relevant pathways and then compared dysregulation in a human model to transcriptomic differences in embryonic and perinatal mice to determine whether dysregulation in an in vitro human model is partially replicated in an in vivo model of HNRNPU-related disorder. Strikingly, we find enrichment of co-dysregulation between 45-day-old human organoids and embryonic, but not perinatal, mice from distinct models of HNRNPU-related disorder. Thus, hnRNPU deficient human organoids may only be suitable to model transcriptional dysregulation in certain cell types within a specific developmental time window. HNRNPU+/− hCOs are significantly smaller than wild-type organoids HNRNPU+/− hCOs show increased number of dysregulated genes in precursor populations Transcriptomic dysregulation in HNRNPU+/− hCOs concordant with embryonic mice Embryonic and perinatal Hnrnpu mutant cortices do not show consistent dysregulation Psychiatry; Biological sciences; Developmental biology; Embryology; Omics; Transcriptomics
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影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
DOI：
10.1016/s1474-4422(15)00199-4
发表时间：
2015-12
期刊：
The Lancet. Neurology
影响因子：
--
作者：
EpiPM Consortium
通讯作者：
EpiPM Consortium
影响因子：
64.5
作者：
Nozawa RS;Boteva L;Soares DC;Naughton C;Dun AR;Buckle A;Ramsahoye B;Bruton PC;Saleeb RS;Arnedo M;Hill B;Duncan RR;Maciver SK;Gilbert N
通讯作者：
Gilbert N
影响因子：
12.3
作者：
Gillentine MA;Wang T;Hoekzema K;Rosenfeld J;Liu P;Guo H;Kim CN;De Vries BBA;Vissers LELM;Nordenskjold M;Kvarnung M;Lindstrand A;Nordgren A;Gecz J;Iascone M;Cereda A;Scatigno A;Maitz S;Zanni G;Bertini E;Zweier C;Schuhmann S;Wiesener A;Pepper M;Panjwani H;Torti E;Abid F;Anselm I;Srivastava S;Atwal P;Bacino CA;Bhat G;Cobian K;Bird LM;Friedman J;Wright MS;Callewaert B;Petit F;Mathieu S;Afenjar A;Christensen CK;White KM;Elpeleg O;Berger I;Espineli EJ;Fagerberg C;Brasch-Andersen C;Hansen LK;Feyma T;Hughes S;Thiffault I;Sullivan B;Yan S;Keller K;Keren B;Mignot C;Kooy F;Meuwissen M;Basinger A;Kukolich M;Philips M;Ortega L;Drummond-Borg M;Lauridsen M;Sorensen K;Lehman A;CAUSES Study;Lopez-Rangel E;Levy P;Lessel D;Lotze T;Madan-Khetarpal S;Sebastian J;Vento J;Vats D;Benman LM;Mckee S;Mirzaa GM;Muss C;Pappas J;Peeters H;Romano C;Elia M;Galesi O;Simon MEH;van Gassen KLI;Simpson K;Stratton R;Syed S;Thevenon J;Palafoll IV;Vitobello A;Bournez M;Faivre L;Xia K;SPARK Consortium;Earl RK;Nowakowski T;Bernier RA;Eichler EE
通讯作者：
Eichler EE
影响因子：
3.6
作者：
Nieto-Estévez V;Hsieh J
通讯作者：
Hsieh J