Chromatin-remodelling factor Brg1 regulates myocardial proliferation and regeneration in zebrafish

Abstract

The zebrafish possesses a remarkable capacity of adult heart regeneration, but the underlying mechanisms are not well understood. Here we report that chromatin remodelling factor Brg1 is essential for adult heart regeneration. Brg1 mRNA and protein are induced during heart regeneration. Transgenic over-expression of dominant-negative Xenopus Brg1 inhibits the formation of BrdU+/Mef2C+ and Tg(gata4:EGFP) cardiomyocytes, leading to severe cardiac fibrosis and compromised myocardial regeneration. RNA-seq and RNAscope analyses reveal that inhibition of Brg1 increases the expression of cyclin-dependent kinase inhibitors such as cdkn1a and cdkn1c in the myocardium after ventricular resection; and accordingly, myocardial-specific expression of dn-xBrg1 blunts myocardial proliferation and regeneration. Mechanistically, injury-induced Brg1, via its interaction with Dnmt3ab, suppresses the expression of cdkn1c by increasing the methylation level of CpG sites at the cdkn1c promoter. Taken together, our results suggest that Brg1 promotes heart regeneration by repressing cyclin-dependent kinase inhibitors partly through Dnmt3ab-dependent DNA methylation.

The long noncoding RNA THRIL knockdown protects hypoxia-induced injuries of H9C2 cells through regulating miR-99a

“…However, in adults, Brg1 is turned off in cardiomyocytes and it is reactivated by cardiac stresses, and preventing Brg1 re-expression decreases hypertrophy [31]. Zebrafish experiment also showed that Brg1 promotes heart regeneration by repressing cyclin-dependent kinase inhibitors partly through Dnmt3ab-dependent DNA methylation [30]. Results herein showed that Brg1 was positively regulated by miR-99a in H9C2 cells, and overexpression of Brg1 attenuated hypoxiainduced cell injuries.…”

“…Brg1 is one of the central ATPase catalytic subunits, which is essential for zygote genome activation, erythropoiesis, cardiac development and neuronal development [30]. In embryos, Brg1 promotes cardiomyocyte proliferation by maintaining Bmp10 and suppressing p57 kip2 expression.…”

Zebrafish heart regeneration: 15 years of discoveries

“…Brg1 expression is strongly induced upon injury in the wound edge, and overexpression of a dominant negative Brg1 blocks cardiomyocyte proliferation. The authors showed that Brg1 is required to prevent expression of cyclin‐dependent kinase inhibitors by increasing DNA methylation in collaboration with the methyltransferase Dnmt3ab (Xiao et al., ). It remains to be explored whether additional epigenetic mechanisms are involved in reactivating cardiomyocyte proliferation.…”

Epigenetic modifications—insight into oligodendrocyte lineage progression, regeneration, and disease

“…The SWI/SNF chromatin‐remodeling factors Brg1 and Brm have been shown to regulate through altering the state of DNA methylation in a context‐dependent manner . DNA methylation is critical for efficient OPC expansion and early onset of differentiation, but not OPC survival , and is also important for efficient remyelination .…”