SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis.
Despite extensive efforts to understand the monogenic contributions to perturbed glucose homeostasis, the complexity of genetic events that fractionally contribute to the spectrum of this pathology remain poorly understood. Proper maintenance of glucose homeostasis is the central feature of a constellation of comorbidities that define the metabolic syndrome. The ability of the liver to balance carbohydrate uptake and release during the feeding-to-fasting transition is essential to the regulation of peripheral glucose availability. The liver coordinates the expression of gene programs that control glucose absorption, storage, and secretion. Herein, we demonstrate that Steroid Receptor Coactivator 2 (SRC-2) orchestrates a hierarchy of nutritionally responsive transcriptional complexes to precisely modulate plasma glucose availability. Using DNA pull-down technology coupled with mass spectrometry, we have identified SRC-2 as an indispensable integrator of transcriptional complexes that control the rate-limiting steps of hepatic glucose release and accretion. Collectively, these findings position SRC-2 as a major regulator of polygenic inputs to metabolic gene regulation and perhaps identify a previously unappreciated model that helps to explain the clinical spectrum of glucose dysregulation.
Interdepartmental Department in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030-3411; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Tiffany
T
Fleet
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Bin
B
Zhang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Fumin
F
Lin
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Bokai
B
Zhu
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Subhamoy
S
Dasgupta
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Erin
E
Stashi
Department of Pediatrics, Gastroenterology, Hepatology & Nutrition, Baylor College of Medicine, Houston, TX 77030-3411;
Bryan
B
Tackett
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411; Department of Pediatrics, Gastroenterology, Hepatology & Nutrition, Baylor College of Medicine, Houston, TX 77030-3411;
Sundararajah
S
Thevananther
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Kimal I
KI
Rajapakshe
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Naomi
N
Gonzales
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Adam
A
Dean
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Jianqiang
J
Mao
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3026;
Nikolai
N
Timchenko
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Anna
A
Malovannaya
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Jun
J
Qin
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Cristian
C
Coarfa
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030-3411;
Francesco
F
DeMayo
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411; Department of Medicine, Baylor College of Medicine, Houston, TX 77030-3411.
Clifford C
CC
Dacso
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411;
Charles E
CE
Foulds
Interdepartmental Department in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030-3411; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030-3411; york@bcm.edu berto@bcm.edu.
Bert W
BW
O'Malley
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030-3411; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030-3411; york@bcm.edu berto@bcm.edu.
Brian
B
York
D000818:Animals; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D055765:Shc Signaling Adaptor Proteins / Q000502:physiology*; D014158:Transcription, Genetic
D055765:Shc Signaling Adaptor Proteins; D005941:Glucokinase; D005947:Glucose
SRC-2; Steroid Receptor Coactivator 2; glucokinase; glucose homeostasis; polygenic disease