Analysis of cardiac differentiation at single cell resolution reveals a requirement of hypertrophic signaling for HOPX transcription

• DOI: 10.1101/229294
• Publication Date: 2017-12-08T06:10:23Z
• Authors: Clayton E Friedman; Quan Nguyen; Samuel W Lukowski; Han Sheng Chiu; Abbigail Helfer; Jason Miklas; Shengbao Suo Suo; Jing-Dong Jackie Han; Pierre Osteil; Guangdun Peng; Naihe Jing; Greg J Baillie; Anne Senabouth; Angelika N Christ; Timothy J Bruxner; Charles E Murry; Emily S Wong; Jun Ding; Yuliang Wang; James Hudson; Hannele Ruohola-B...; Ziv Bar-Joseph; Patrick P L Tam; Joseph E Powell; Nathan J Palpant
• Keywords: 0301 basic medicine; 03 medical and health sciences

AbstractDifferentiation into diverse cell lineages requires the orchestration of gene regulatory networks guiding diverse cell fate choices. Utilizing human pluripotent stem cells, we measured expression dynamics of 17,718 genes from 43,168 cells across five time points over a thirty day time-course ofin vitrocardiac-directed differentiation. Unsupervised clustering and lineage prediction algorithms were used to map fate choices and transcriptional networks underlying cardiac differentiation. We leveraged this resource to identify strategies for controllingin vitrodifferentiation as it occursin vivo. HOPX, a non-DNA binding homeodomain protein essential for heart developmentin vivowas identified as dys-regulated inin vitroderived cardiomyocytes. Utilizing genetic gain and loss of function approaches, we dissect the transcriptional complexity of the HOPX locus and identify the requirement of hypertrophic signaling for HOPX transcription in hPSC-derived cardiomyocytes. This work provides a single cell dissection of the transcriptional landscape of cardiac differentiation for broad applications of stem cells in cardiovascular biology.