Role of Chromatin Organizing Proteins SATB1/2 in Insulin like Growth Factor (IGF) Signaling

Abstract

Calorie restriction as a regime to regulate organismal life span has been known to be effective across a wide range of model organism including humans. Insulin and Insulin like growth factor (IGF) mediated signaling is one of the primary sensors of metabolic flux in several model organisms and is invoked during regulation of organismal life span by calorie restriction. Extensive research over the past two decades indicates that calorie restriction mediated increase in life span is caused by the down regulation of the IGFR mediated signaling. The down regulation of the IGFR pathway prevents phosphorylation of the FOXO family of transcription factors by both Akt/PI3K and JNK pathways. Phosphorylation leads to the retention of these factors in the cytosol due to their association with protein chaperones. The loss of the phosphate groups on the FOXO’s leads to the disruption of their association with protein chaperones followed by their translocation into the nucleus. The transcriptional activity resident downstream of IGF signaling is mediated via Forkhead family (FOXO1) transcription factors (FOXO). FOXO1 regulates the transcription of various insulin responsive (IR) genes by its association with a conserved DNA element called the Insulin Responsive Sequence (IRS). In addition, this processes is also likely to involve the participation of unknown transcriptional activators and/or repressors. We report the discovery of Special AT-rich Binding (SATB) proteins as novel repressors of transcription from IRS sequences. Our study shows the physical interaction between global chromatin organizing SATB1 protein and insulin responsive sequence (IRS) present. We also demonstrate a possible feedback mechanism in the form of a FOXO3a footprint on SATB1 promoter indicating that SATB proteins and IGF signaling regulate each other.