Kinetic networks identify TWIST2 as a key regulatory node in adipogenesis.
Kinetic networks identify TWIST2 as a key regulatory node in adipogenesis.
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DOI：
10.1101/gr.277559.122
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发表时间：
2023-03
期刊：
影响因子：
7
通讯作者：
Guertin, Michael J.
中科院分区：
文献类型：
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作者：
Dutta, Arun B.;Lank, Daniel S.;Przanowska, Roza K.;Przanowski, Piotr;Wang, Lixin;Nguyen, Bao;Walavalkar, Ninad M.;Duarte, Fabiana M.;Guertin, Michael J.
脂肪细胞导致代谢紊乱，如肥胖、糖尿病和动脉粥样硬化。先前对驱动脂肪形成的转录网络的描述忽略了瞬时作用的转录因子（TFs）、基因和调节元件，而这些转录因子是适当分化所必需的。此外，传统的基因调控网络既没有提供关于单个调控元件-基因关系的机制细节，也没有提供定义关键调控因子优先级的调控等级所需的时间信息。为了解决这些缺点，我们整合了动态染色质可及性（ATAC-seq）和新生转录（PRO-seq）数据，生成了描述TF结合事件及其对靶基因表达的影响的时间可解网络。我们的数据表明，TF家族相互合作或相互拮抗调节脂肪形成。RNA聚合酶密度的室室建模量化了单个tf如何在机制上促进转录的不同步骤。糖皮质激素受体通过诱导RNA聚合酶暂停释放激活转录，而SP和AP-1因子影响RNA聚合酶启动。我们发现Twist2是一种以前未被发现的脂肪细胞分化效应。我们发现TWIST2作为3T3-L1和原代前脂肪细胞分化的负调节因子。我们证实，Twist2基因敲除小鼠在皮下和棕色脂肪组织中的脂质储存受损。先前对Twist2基因敲除小鼠和Setleis综合征Twist2−/−患者的表型分析表明，皮下脂肪组织存在缺陷。这种网络推理框架是解释复杂生物现象的一种强大而通用的方法，可以应用于广泛的细胞过程。
Adipocytes contribute to metabolic disorders such as obesity, diabetes, and atherosclerosis. Prior characterizations of the transcriptional network driving adipogenesis have overlooked transiently acting transcription factors (TFs), genes, and regulatory elements that are essential for proper differentiation. Moreover, traditional gene regulatory networks provide neither mechanistic details about individual regulatory element–gene relationships nor temporal information needed to define a regulatory hierarchy that prioritizes key regulatory factors. To address these shortcomings, we integrate kinetic chromatin accessibility (ATAC-seq) and nascent transcription (PRO-seq) data to generate temporally resolved networks that describe TF binding events and resultant effects on target gene expression. Our data indicate which TF families cooperate with and antagonize each other to regulate adipogenesis. Compartment modeling of RNA polymerase density quantifies how individual TFs mechanistically contribute to distinct steps in transcription. The glucocorticoid receptor activates transcription by inducing RNA polymerase pause release, whereas SP and AP-1 factors affect RNA polymerase initiation. We identify Twist2 as a previously unappreciated effector of adipocyte differentiation. We find that TWIST2 acts as a negative regulator of 3T3-L1 and primary preadipocyte differentiation. We confirm that Twist2 knockout mice have compromised lipid storage within subcutaneous and brown adipose tissue. Previous phenotyping of Twist2 knockout mice and Setleis syndrome Twist2−/− patients noted deficiencies in subcutaneous adipose tissue. This network inference framework is a powerful and general approach for interpreting complex biological phenomena and can be applied to a wide range of cellular processes.
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影响因子：
64.5
作者：
DISTEL, RJ;RO, HS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM
DOI：
10.1073/pnas.91.1.192
发表时间：
1994-01-04
影响因子：
11.1
作者：
GILL, G;PASCAL, E;TJIAN, R
通讯作者：
TJIAN, R
影响因子：
5.8
作者：
Anderson, Warren D.;Duarte, Fabiana M.;Guertin, Michael J.
通讯作者：
Guertin, Michael J.
影响因子：
11.8
作者：
Bialek, P;Kern, B;Karsenty, G
通讯作者：
Karsenty, G
影响因子：
64.8
作者：
通讯作者：
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