Down-regulation of Beclin1 promotes direct cardiac reprogramming

Abstract

Direct reprogramming of fibroblasts to alternative cell fates by forced expression of transcription factors offers a platform to explore fundamental molecular events governing cell fate identity. The discovery and study of induced cardiomyocytes (iCMs) not only provides alternative therapeutic strategies for heart disease but also sheds lights on basic biology underlying CM fate determination. The iCM field has primarily focused on early transcriptome and epigenome repatterning, whereas little is known about how reprogramming iCMs remodel, erase, and exit the initial fibroblast lineage to acquire final cell identity. Here, we show that autophagy-related 5 (Atg5)–dependent autophagy, an evolutionarily conserved self-digestion process, was induced and required for iCM reprogramming. Unexpectedly, the autophagic factor Beclin1 (Becn1) was found to suppress iCM induction in an autophagy-independent manner. Depletion of Becn1 resulted in improved iCM induction from both murine and human fibroblasts. In a mouse genetic model, Becn1 haploinsufficiency further enhanced reprogramming factor–mediated heart function recovery and scar size reduction after myocardial infarction. Mechanistically, loss of Becn1 up-regulated Lef1 and down-regulated Wnt inhibitors, leading to activation of the canonical Wnt/β-catenin signaling pathway. In addition, Becn1 physically interacts with other classical class III phosphatidylinositol 3-kinase (PI3K III) complex components, the knockdown of which phenocopied Becn1 depletion in cardiac reprogramming. Collectively, our study revealed an inductive role of Atg5-dependent autophagy as well as a previously unrecognized autophagy-independent inhibitory function of Becn1 in iCM reprogramming.

Association of DNA methylation and transcriptome reveals epigenetic etiology of heart failure

“…6F), including the Kat family and Esco family. In addition, the promoter region of another acetylation transferase-Lef1 (distance to TSS: − 82) shows significant changes and upregulation in RNA expression; this supports the evidence that Lef1 is a regulator for cardiac reprogramming and cardiac hypertrophy (Lai et al, 2019;Wang et al, 2020) (Fig. 6E).…”

Advanced Technologies to Target Cardiac Cell Fate Plasticity for Heart Regeneration

“…Moreover, AKT1 overexpression was not associated with altered proliferation or apoptosis [107]. The role of mTORC1, however, is still controversial as Wang et al observed enhanced reprogramming efficiency following rapamycin treatment, which they attributed to increased autophagy due to mTORC1 inhibition [109], in contrast to the impaired reprogramming observed by Zhou et al upon mTORC1 inhibition [107].…”

Resuscitating the Field of Cardiac Regeneration: Seeking Answers from Basic Biology

“…Autophagic factor Becn1 suppressed iCMs induction in an autophagy-independent manner, meanwhile depletion of Becn1 resulted in improved iCMs induction from both murine and human fibroblasts. [169] Moreover, the induction effects from Becn1 knockdown is independent of autophagy induction due to activation of the canonical Wnt/β-catenin pathway. [169] In addition, direct in vivo reprogramming have led to the generation of functionally maturer iCMs than those obtained in vitro condition.…”

“…[169] Moreover, the induction effects from Becn1 knockdown is independent of autophagy induction due to activation of the canonical Wnt/β-catenin pathway. [169] In addition, direct in vivo reprogramming have led to the generation of functionally maturer iCMs than those obtained in vitro condition. [170][171][172] Therefore, it is suggested that local environment plays significant role in the efficacy of fibroblast direct reprogramming.…”