Baf60c is essential for function of BAF chromatin remodelling complexes in heart development

Abstract

Tissue-specific transcription factors regulate several important aspects of embryonic development. They must function in the context of DNA assembled into the higher-order structure of chromatin. Enzymatic complexes such as the Swi/Snf-like BAF complexes remodel chromatin to allow the transcriptional machinery access to gene regulatory elements. Here we show that Smarcd3, encoding Baf60c, a subunit of the BAF complexes, is expressed specifically in the heart and somites in the early mouse embryo. Smarcd3 silencing by RNA interference in mouse embryos derived from embryonic stem cells causes defects in heart morphogenesis that reflect impaired expansion of the anterior/secondary heart field, and also results in abnormal cardiac and skeletal muscle differentiation. An intermediate reduction in Smarcd3 expression leads to defects in outflow tract remodelling reminiscent of human congenital heart defects. Baf60c overexpressed in cell culture can mediate interactions between cardiac transcription factors and the BAF complex ATPase Brg1, thereby potentiating the activation of target genes. These results reveal tissue-specific and dose-dependent roles for Baf60c in recruiting BAF chromatin remodelling complexes to heart-specific enhancers, providing a novel mechanism to ensure transcriptional regulation during organogenesis.

Mechanisms of ATP dependent chromatin remodeling

“…The role of SWI/SNF by all indications is far reaching. In mammals it is involved in many developmental programs such as muscle [19][20][21][22], heart [23], blood [24], skeletal [25], neuron [26][27][28][29], adipocyte [30], liver [31] and immune system/Tcell development [32,33]. Yeast SWI/SNF has been shown to be involved in an early step in homologous recombination (HR) while RSC promotes HR at the stage of strand invasion [34,35].…”

Multimodal imaging of mouse development: Tools for the postgenomic era

“…Since the initial study of mouse embryos in utero (Turnbull et al, 1995a), ultrasonography has been used for imaging and staging early postimplantation embryos in utero (Turnbull, 1999;Chang et al, 2003), and both transcutaneous and transuterine UBM has become a standard method for assessing normal and defective cardiovascular development in mice (Srinivasan et al, 1998;Fatkin et al, 1999;Phoon et al, 2000Phoon et al, , 2002Phoon et al, , 2004Ji et al, 2003;Phoon and Turnbull, 2003;Lickert et al, 2004;Mai et al, 2004;Ji and Phoon, 2005). Many of these studies have also used Doppler echocardiography, a highly sensitive method for measuring the direction and velocity of blood flow (see Phoon and Turnbull, 2003, for review).…”

“…In knockdown embryos, an abnormal outflow tract (OFT) and right ventricle (RV) are apparent. LV, left ventricle (Lickert et al, 2004). Image kindly provided by Jun Takeuchi, Hospital for Sick Children, Toronto, Ontario, Canada.…”

“…Figure 4 shows a rendered OPT projection of fluorescent whole-mount in situ hybridizations of 9.5 dpc embryos, showing the detail one can achieve with this method (Fig. 4, see Lickert et al, 2004). Improvements to reconstruction algorithms recently have been reported that decrease the contribution from various types of noise associated with image acquisition (Walls et al, 2005).…”

“…Both EFIC and OPT have been used to evaluate development in normal and mutant mouse embryos in several studies, and the reconstruction of complex 3D structures has revealed subtle changes in structure (Weninger and Mohun, 2002;Hecksher-Sorensen et al, 2004;Lickert et al, 2004;Meilhac et al, 2004;Rosenthal et al, 2004;Smyth et al, 2004;Wilkie et al, 2004;Takeuchi et al, 2005a;Weninger et al, 2005). The ability to collect 3D gene and protein expression data also makes it possible to create searchable atlases of expression data (Sarma et al, 2005), allowing for a greater appreciation of how changes in 3D morphology relate to changes at a molecular level.…”