HBL1 Is a Human Long Noncoding RNA that Modulates Cardiomyocyte Development from Pluripotent Stem Cells by Counteracting MIR1

Abstract

Summary Cardiogenesis processes in human and animals have differential dynamics, suggesting the existence of species–specific regulators during heart development. However, it remains a challenge to discover the human-specific cardiac regulatory genes, given that most coding-genes are conserved. Here, we report the identification of a human-specific long noncoding RNA, Heart Brake LncRNA 1 (HBL1), which regulates cardiomyocyte development from human induced pluripotent stem cells (hiPSCs). Overexpression of HBL1 repressed, whereas knockdown and knockout of HBL1 increased cardiomyocyte differentiation from hiPSCs. HBL1 physically interacted with miR-1 in an AGO2 complex. Disruption of miR-1 binding sites in HBL1 showed similar effect as HBL1 knockout. SOX2 bound to HBL1 promoter and activated its transcription. Knockdown of SOX2 in hiPSCs lead to decreased HBL1 expression, and increased cardiomyocyte differentiation efficiency. Thus, HBL1 can play a modulator role in fine-tuning human-specific cardiomyocyte development by forming a regulatory network with SOX2 and miR-1.

Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells

“…In further analyzing genes differentially expressed in our HERV-H knockout lines, we discovered that the human-specific long-coding RNA (lncRNA), Heart Brake ( HBL1 ), which has been reported recently to suppress cardiomyocyte differentiation 45 , was also significantly reduced in the HERV-H1-KO hESCs ( Supplementary Fig. 9g ).…”

The Long Noncoding RNA Lncenc1 Maintains Naive States of Mouse ESCs by Promoting the Glycolysis Pathway

“…As one of the most commonly used cell models for lncRNA studies, PSCs have been extensively profiled for RNA expression, epigenetic modifications, and RNA-protein interactions ( Guttman et al., 2009 , Guttman et al., 2011 , Kelley and Rinn, 2012 ). Functional studies have indicated that lncRNAs are involved in the self-renewal of PSCs through regulating key pluripotency factors ( Kaneko et al., 2014 , Perry and Ulitsky, 2016 , Sheik Mohamed et al., 2010 ), mediating chromatin modifications ( da Rocha et al., 2014 , Jain et al., 2016 , Lin et al., 2014 ), or sponging/counteracting microRNAs ( Liu et al., 2017 , Wang et al., 2013 ). However, the lists of potentially functional lncRNAs in ESCs that have been reported by different studies overlap poorly ( Guttman et al., 2011 , Kaneko et al., 2014 ), which suggests that the functions of lncRNAs in PSCs are still not yet fully understood.…”

LncRNA Functions as a New Emerging Epigenetic Factor in Determining the Fate of Stem Cells

“…Heart Brake LncRNA 1 is a human-specific lncRNA related to cardiomyocyte differentiation. HBL1 over-expression suppresses cardiomyocyte differentiation by down-regulating GATA4, CTNT, NKX2.5, TBX5, TBX20 and α-MHC expression while its silencing has opposite effects (Liu et al, 2017). Mechanistically, HBL1 can interact and sponge miR-1, a key cardiomyocyte differentiation promoter, to impair cardiomyocyte differentiation (Lu T.Y.…”

“…Mechanistically, HBL1 can interact and sponge miR-1, a key cardiomyocyte differentiation promoter, to impair cardiomyocyte differentiation (Lu T.Y. et al, 2013;Liu et al, 2017). LncRNA Braveheart (Bvht) is exclusively expressed in the heart and can promote cardiovascular lineage commitment of mESCs by activating functional upstream genes of the MesP1, a permissive regulator of multipotent cardiovascular progenitor (Bondue et al, 2008(Bondue et al, , 2011.…”