DEVELOPMENT TIPping Toward Muscle or Fat

Stretch plays an important role in differentiation in developing embryos, and in adult tissues, stretch triggers various cellular responses. Jakkaraju et al. identified a new protein family of chromatin remodeling enzymes called TIP, for tension-induced or -inhibited proteins. The abundance of TIP-1 was increased [detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting] when undifferentiated mouse lung mesenchymal cells were subjected to stretch and persisted when these cells differentiated into smooth muscle myoblasts in response to stretch. TIP-3 was present, but unaffected by stretch, in the undifferentiated progenitor cells and was absent from the smooth muscle myoblasts. Although both TIP-1 and TIP-3 were present in the cytoplasm and nucleus of the progenitor cells, stretch promoted the accumulation of TIP-1 in the nuclei of smooth muscle myoblasts. Overexpression of TIP-1 or TIP-3 stimulated myogenic or adipogenic gene expression, respectively, in lung progenitor cells. Inhibition of TIP-1 using RNA interference converted smooth muscle myoblasts into lipoblasts (an adipose-related cell type). Chromatin immunoprecipitation (ChIP) experiments indicated that TIP-1 was recruited to the serum response factor (SRF) promoter (a gene involved in myogenesis) and that TIP-3 was recruited to the PPAR2 promoter (a gene involved in adipogenesis). Furthermore, the promoters also possessed acetylated histone H4, and in vitro assays with immunopurified TIP-1 or TIP-3 showed that these proteins have histone acetyltransferase (HAT) activity. Recruitment to the promoters required the nuclear receptor binding boxes (NRBs) of TIP-1 and TIP-3, which is consistent with a requirement for interaction with other transcription factors for promoter recruitment (neither TIP-1 nor TIP-3 directly bound DNA based on electrophoretic mobility shift assay). These results suggest that in response to stretch, amounts of TIP-1 are increased, allowing it to serve as a coregulator and HAT for transcriptional activation of myogenic genes. In the absence of stretch, these same progenitor cells possess TIP-3, which allows an adipogenic differentiation pathway to proceed.

S. Jakkaraju, X. Zhe, D. Pan, R. Choudhury, L. Schuger, TIPs are tension-responsive proteins involved in myogenic versus adipogenic differentiation. Dev. Cell 9, 39-49 (2005). [PubMed]