ZNF281 enhances cardiac reprogramming by modulating cardiac and inflammatory gene expression

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Molecular Biology

Background:

• Direct reprogramming of fibroblasts to cardiomyocytes offers a promising strategy for cardiac repair after injury.
• Existing methods using AKT1 and cardiogenic transcription factors (AGHMT) are inefficient in adult fibroblasts.

Purpose of the Study:

• To identify novel regulators that enhance adult fibroblast to cardiomyocyte reprogramming.
• To understand the interplay between cardiac and inflammatory pathways in this process.

Main Methods:

• Unbiased screening of transcription factors and cytokines in adult mouse fibroblasts.
• Genome-wide association studies to identify ZNF281 binding sites.
• Analysis of inflammatory gene expression and blockade of inflammatory pathways.

Main Results:

• Zinc finger transcription factor 281 (ZNF281) was identified as a potent stimulator of cardiac reprogramming.
• ZNF281 associates with GATA4 on cardiac enhancers and suppresses inflammatory gene expression.
• Blocking inflammatory pathways or inhibiting the NuRD complex (associated with ZNF281) enhanced cardiac gene expression.

Conclusions:

• ZNF281 plays a critical role at the intersection of cardiac and inflammatory gene programs.
• Inflammatory signaling antagonizes fibroblast to cardiomyocyte reprogramming.
• Targeting ZNF281 and inflammatory pathways may improve direct cardiac reprogramming strategies.