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Epicardial HDAC3 promotes myocardial growth through a novel microRNA pathway

Jihyun Jang, Guang Song, Qinshan Li, Xiaosu Song, Chenleng Cai, Sunjay Kaushal, Deqiang Li

Preprint posted on September 16, 2021 https://www.biorxiv.org/content/10.1101/2021.09.16.460538v1?ct=

Deciphering the epicardial signals that promote myocardial growth

Selected by Anna Meier

Background

The heart muscle, also called the myocardium, is covered by an outer layer of mesothelial cells called the epicardium. During embryonic development, a subset of epicardial cells undergo an epithelial-to-mesenchymal transition (EMT) to give rise to epicardial-derived cells (EPDCs) that migrate into the myocardium and mainly differentiate into fibroblasts and vascular smooth muscle cells. In addition to these cellular contributions, the epicardium significantly influences the morphogenesis of the myocardium. Epicardial cells secrete growth factors such as IGF2 and FGF9 that stimulate cardiomyocyte proliferation, thereby promoting the formation of a subepicardial compact zone that is necessary for proper cardiac function1,2. Here, Jang and colleagues identified an upstream regulatory mechanism controlled by histone deacetylase 3 (HDAC3), an enzyme that catalyzes the removal of acetyl groups from lysine residues in histone tails.

 

Key findings

The authors first observed that the conditional knockout (KO) of Hdac3 in WT1+ epicardial cells at E8.5 led to an abnormally thin compact layer due to reduced cardiomyocyte proliferation. Similarly, embryonic cardiomyocytes exposed to the supernatant of Hdac3 KO immortalized murine embryonic epicardial cells (MECs) in vitro showed reduced proliferation compared to those exposed to the supernatant of wild-type (WT) MECs. This could be attributed to lower secretion of FGF9 and IGF2 by Hdac3 KO MECs, suggesting transcriptional regulation of these factors by HDAC3.

As microRNAs that post-transcriptionally regulate gene expression are common downstream targets of HDACs, the authors next performed microRNA sequencing in Hdac3 KO and WT MECs. Of the 42 microRNAs upregulated in the absence of Hdac3, 11 had putative binding sites in Fgf9 or Igf2. Treating WT MECs with synthetic mimics of these microRNAs showed that two of them, mir-322 and mir-503, significantly inhibited the expression of both Fgf9 and Igf2. Importantly, these microRNAs were also found upregulated in Hdac3 KO hearts.

The authors hypothesized that HDAC3 may regulate mir-322 and mir-503 expression via the histone modification H3K27Ac, which is a marker for active promoters and a direct downstream target of HDAC3. Indeed, chromatin immunoprecipitation coupled to detection by real-time quantitative PCR (ChIP-qPCR) showed that Hdac3 deletion was associated with increased binding of H3K27Ac to the promoter region of mir-322/mir-503, which are encoded as one cluster located in chromosome X. A mir-322/mir-503 promoter luciferase reporter assay confirmed that promoter activity was increased in MECs lacking Hdac3 or treated with a selective HDAC3 deacetylase inhibitor. This led to the authors’ proposed model in which epigenetic repression of mir-322/-503 by HDAC3 allows epicardial cells to produce sufficient levels of the growth factors FGF9 and IGF2 to promote cardiomyocyte proliferation and the formation of the compact layer (Figure 1).

 

Figure 1: Proposed mechanism for the regulation of myocardial growth by epicardial signaling.  Adapted from Figure 7 of this preprint.

 

Why I chose this preprint

I chose this preprint because I have a particular interest in the role of the epicardium in heart development and repair. The epicardium is central to heart regeneration processes in zebrafish and neonatal mice, which, in contrast to adult humans, have the capacity to extensively regenerate cardiomyocytes lost through injury3,4. As this involves the re-activation of embryonic epicardial programs, insights from development could lead to new therapeutic approaches.

I also appreciated that the authors took the time to confirm each finding by several different methods, which is unfortunately often neglected.

 

References

  1. Shen, H. et al. Extracardiac control of embryonic cardiomyocyte proliferation and ventricular wall expansion. Cardiovasc. Res. 105, 271–8 (2015).
  2. Lavine, K. J. et al. Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo. Dev. Cell 8, 85–95 (2005).
  3. Poss, K. D., Wilson, L. G. & Keating, M. T. Heart regeneration in zebrafish. Science 298, 2188–90 (2002).
  4. Porrello, E. R. et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–80 (2011).

Tags: cardiogenesis, epicardium

Posted on: 14th October 2021

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Author's response

Jihyun Jang shared

  1. You show that one of the effects of Hdac3 deletion in epicardial cells is a decrease in the number of EPDCs. Do you know if this is due to a role of HDAC3 in epicardial EMT?

EPDCs migrate into compact myocardium and eventually differentiate into fibroblasts and other vascular cell lineages following EMT. Indeed, we found that gene expression of EMT markers such as Snail1 and TWIST1 were significantly decreased in epicardial Hdac3 KO hearts as compared to control hearts, suggesting the role of epicardial Hdac3 in EMT.

 

  1. The treatment of MECs with different microRNAs showed that other microRNAs also led to the downregulation of Fgf9 and/or Igf2 (such as 466-5p, 362-3p), are you interested in investigating their potential role in this signaling pathway? Do you expect the different microRNAs to have redundant functions?

It is possible that other miRNAs besides miR-322/503 also regulate these growth factors. For example, another candidate miR466-5p is known as a tumor suppressor (PMID: 28125091, 29338680) and the repressor of lymphangiogenesis (PMID: 25573115), suggesting its role in regulating cell growth. We will study their potential roles in this process in the future.

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