LEF1 IS A CRITICAL SOMATIC TRANSCRIPTION FACTOR FOR THE MECHANICAL INDUCTION OF CELLULAR REPROGRAMMING

Abstract

Seminal reprogramming studies have demonstrated the importance of biochemical factors in dedifferentiating somatic cells. Recent work showed that the laterally confined growth of fibroblasts may induce dedifferentiation. However, the molecular mechanisms underlying are poorly understood. In this work, we identify Lef1 as a critical somatic transcription factor for the mechanical regulation of reprogramming. A network optimization method applied to time-lapse RNA-seq data identifies Lef1 as a key regulator. Lef1 knockdown results in the down-regulation of reprogramming efficiency. Moreover, Lef1 directly interacts with the promoter regions of some reprogramming factors. We also evaluate the potential upstream activation pathways of Lef1, thereby identifying that Smad4 may be critical. Collectively, we describe an important mechanotransduction pathway, including Lef1, which upon activation, through progressive lateral cell confinement, results in the reprogramming of fibroblasts. This work will contribute towards understanding the cellular mechanical control in cell state transition.