Screening of histone modulators small molecule library reveals Kdm5b as a major epigenetic modulator of cell cycle gene expression in Cardiomyocyte

In this study, through a small molecule screening, we defined the histone lysine demethylase, Kdm5b, as a major epigenetic driver that controls the CM cell cycle gene expression in neonatal stage and can be reintroduced in adult CMs to induce cell cycle. Mechanistically, RNAseq and CUT&RUN analyses of Kdm5b KD in NMCM P1 revealed that Kdm5b modulates the expression and the enrichment of H3K4me3 methylation around the regulatory regions of the genes involved in cell cycle. Overall design: RNA sequencing profiling in postnatal P1 control Kdm5b FF mice heart and Kdm5b cardiac specific KO mice heart

本研究通过小分子筛选，将组蛋白赖氨酸去甲基化酶Kdm5b确定为调控新生期心肌细胞（CM）细胞周期基因表达的核心表观遗传驱动因子，且可在成年心肌细胞中重新导入以诱导细胞周期激活。
机制分析显示，对出生后1天新生小鼠心肌细胞（NMCM P1）中的Kdm5b敲低（KD）样本开展RNA测序（RNAseq）与CUT&RUN分析后发现，Kdm5b可调控细胞周期相关基因调控区域周围的基因表达水平，以及组蛋白H3赖氨酸4三甲基化（H3K4me3）的富集程度。
实验整体设计：对出生后1天的Kdm5b flox/flox（FF）对照小鼠心脏与心肌特异性敲除（KO）小鼠心脏进行RNA测序转录组分析。