STAG2 cohesin is essential for heart morphogenesis

Abstract

30The distinct functions of cohesin complexes carrying STAG1 or STAG2 need to be unraveled. 31 STAG2 is commonly mutated in cancer and germline mutations have been identified in 32 cohesinopathy patients. To better understand the underlying pathogenic mechanisms, we here 33 report the consequence of Stag2 ablation in mice. STAG2 is largely dispensable in adults and its 34 tissue-wide inactivation does not lead to tumors but reduces fitness and affects both hematopoiesis 35 and intestinal homeostasis. STAG2 is also dispensable for murine embryonic fibroblasts in vitro. 36 In contrast, null embryos die by mid gestation showing global developmental delay and heart 37 defects. Histopathological analysis and RNA-sequencing unveiled that STAG2 is required both for 38 proliferation and regulation of cardiac transcriptional programs and in its absence, secondary heart 39 field progenitors fail to enter the heart tube. These results provide compelling evidence on cell-and 40 tissue-specific roles of the two cohesin complexes and how their dysfunction contributes to disease. 41 42 Given the growing importance of STAG2 in human disease, we generated a Stag2 conditional knock 91 out (cKO) mouse strain to identify the consequences of eliminating cohesin-STAG2 in cells, 92 embryos and adult tissues. 93 94

Three-dimensional chromatin organization in cardiac development and disease

“…A specific subset of the cohesin complex was also recently reported to be essential for heart morphogenesis. Indeed, global knockout of Stag2, but not its homologous Stag1 [87], impaired atrial and ventricular septation, right ventricle development, and outflow tract morphogenesis [88]. Distinctly from the Ctcf knockout model, this phenotype appeared to result from the combination of reduced cellular proliferation and defective migration of second heart field progenitors.…”