YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis in Vivo

Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause of death. Here, we show that an active version of the Hippo pathway effector YAP, termed YAP5SA, partially reprograms adult mouse CMs to a more fetal and proliferative state. One week after induction, 19% of CMs that enter S-phase do so twice, CM number increases by 40%, and YAP5SA lineage CMs couple to pre-existing CMs. Genomic studies showed that YAP5SA increases chromatin accessibility and expression of fetal genes, partially reprogramming long-lived somatic cells in vivo to a primitive, fetal-like, and proliferative state. We isolated cardiomyocyte nuclei from control and YAP5SA animals and performed nuclear RNA-seq (nucRNA-seq), ATAC-seq, and 4C-seq.

特化的成体体细胞，例如心肌细胞（cardiomyocytes，简称CMs），具有高度分化的特性且增殖更新能力极弱，这是疾病与衰老引发器官衰竭的核心原因之一。作为人体内更新能力最弱的细胞类群之一，心肌细胞每年的更新率仅约1%。鉴于心肌细胞更新周转能力低下，心力衰竭已成为全球首要致死病因。本研究发现，经活化改造的Hippo通路效应蛋白YAP（命名为YAP5SA）可将成年小鼠的心肌细胞部分重编程为更接近胎儿期的增殖状态。诱导表达一周后，19%的进入S期的心肌细胞可完成两轮DNA合成，心肌细胞总数增加40%，且表达YAP5SA的心肌细胞谱系可与原生心肌细胞形成功能耦联。基因组学研究表明，YAP5SA可提升染色质开放程度并激活胎儿基因的表达，在活体中将长寿体细胞部分重编程为原始的、类似胎儿期的增殖状态。本研究从对照组与YAP5SA组动物中分离心肌细胞核，分别开展了核RNA测序（nucRNA-seq）、ATAC测序（ATAC-seq）及4C测序（4C-seq）。