PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle

Abstract

Background: Left ventricular noncompaction cardiomyopathy (LVNC) was discovered half a century ago as a cardiomyopathy with excessive trabeculation and a thin ventricular wall. In the decades since, numerous studies have demonstrated that LVNC primarily impacts left ventricles (LVs), and is often associated with LV dilation and dysfunction. However, owing in part to the lack of suitable mouse models that faithfully mirror the selective LV vulnerability in patients, mechanisms underlying susceptibility of LV to dilation and dysfunction in LVNC remain unknown. Genetic studies have revealed that deletions and mutations in PRDM16 cause LVNC, but previous conditional Prdm16 knockout mouse models do not mirror the LVNC phenotype in patients, and importantly, the underlying molecular mechanisms by which PRDM16 deficiency causes LVNC are still unclear. Methods: Prdm16 cardiomyocyte (CM)-specific knockout ( Prdm16 cKO ) mice were generated and analyzed for cardiac phenotypes. RNA sequencing and ChIP sequencing were performed to identify direct transcriptional targets of PRDM16 in CMs. Single cell RNA sequencing in combination with Spatial Transcriptomics were employed to determine CM identity at single cell level. Results: CM-specific ablation of Prdm16 in mice caused LV-specific dilation and dysfunction, as well as biventricular noncompaction, which fully recapitulated LVNC in patients. Mechanistically, PRDM16 functioned as a compact myocardium-enriched transcription factor, which activated compact myocardial genes while repressing trabecular myocardial genes in LV compact myocardium. Consequently, Prdm16 cKO LV compact myocardial CMs shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial CMs and/or neurons. Chamber-specific transcriptional regulation by PRDM16 was in part due to its cooperation with LV-enriched transcription factors Tbx5 and Hand1. Conclusions: These results demonstrate that disruption of proper specification of compact CM may play a key role in the pathogenesis of LVNC. They also shed light on underlying mechanisms of LV-restricted transcriptional program governing LV chamber growth and maturation, providing a tangible explanation for the susceptibility of LV in a subset of LVNC cardiomyopathies.

Dynamic Spatiotemporal Expression Pattern of the Senescence-Associated Factor p16Ink4a in Development and Aging

“…For example, overexpression of p16 slowed cell cycle progression in the G0/G1 phase and induced erythroid lineage differentiation [85], which might correspond to the early p16 expression in embryonic mouse livers [86]. Lack of p16 is linked to increased cardiomyocyte proliferation [80], while lower cardiomyocyte proliferation, differentiation, and specification are required for myocardial compaction [87,88], which coincides with our observed cardiac p16 expression.…”

Twist1 regulates macrophage plasticity to promote renal fibrosis through galectin-3

“…ChIP assays were performed as previously described [ 62 ]. Briefly, the recovered supernatants were incubated with a rabbit anti-Twist1 antibody (#50887, Abcam, Cambridge, United Kingdom) or an isotype control IgG (BD Biosciences, Franklin Lake, NJ, USA) for 2 h in the presence of herring sperm DNA and protein A/G magnetic beads.…”

Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children—A Single Reference Center Experience

“…The mechanisms leading to the LVNC phenotype mostly remain unclear, though some authors have pointed to an abnormal cardiac embryogenesis resulting from the intrauterine arrest of normal ventricular myocardium maturation and compaction [ 8 ]. Recent findings from Wu et al [ 9 ] indicated the improper transcriptional specification of compact or trabecular cardiomyocytes as a potential common mechanism in LVNC development.…”