TY - JOUR T1 - Kinetic networks identify Twist2 as a key regulatory node in adipogenesis JF - bioRxiv DO - 10.1101/2021.11.17.469040 SP - 2021.11.17.469040 AU - Arun B. Dutta AU - Daniel S. Lank AU - Róża K. Przanowska AU - Piotr Przanowski AU - Lixin Wang AU - Bao Nguyen AU - Ninad M. Walavalkar AU - Fabiana M. Duarte AU - Michael J. Guertin Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/12/03/2021.11.17.469040.abstract N2 - Adipocytes contribute to metabolic disorders such as obesity, diabetes, and atherosclerosis. Prior characterizations of the transcriptional network driving adipogenesis overlook 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 RE-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. Glucocorticoid receptor activates transcription by inducing RNA polymerase pause release while SP and AP1 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.Competing Interest StatementThe authors have declared no competing interest. ER -