Sci. STKE, 12 July 2005
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]
Citation: TIPping Toward Muscle or Fat. Sci. STKE 2005, tw255 (2005).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882