Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis

• Published in: Cell reports (Cambridge) 2017-08, Vol.20 (7), p.1597-1608
• Main Authors: Palpant, Nathan J., Wang, Yuliang, Hadland, Brandon, Zaunbrecher, Rebecca J., Redd, Meredith, Jones, Daniel, Pabon, Lil, Jain, Rajan, Epstein, Jonathan, Ruzzo, Walter L., Zheng, Ying, Bernstein, Irwin, Margolin, Adam, Murry, Charles E.
• Format: Article
• Language: English
• Subjects: Algorithms; beta Catenin - genetics; beta Catenin - metabolism; cardiac; cardiovascular; Cell Differentiation; Cell Lineage - genetics; Chromatin - chemistry; Chromatin - metabolism; chromatin dynamics; CRISPR-Cas Systems; differentiation; Endothelial Cells - cytology; Endothelial Cells - metabolism; epigenetics; Fluorescent Dyes - chemistry; Fluorescent Dyes - metabolism; Genes, Reporter; genome engineering; hematopoiesis; Hematopoiesis - genetics; Homeodomain Proteins - genetics; Human Embryonic Stem Cells - cytology; Human Embryonic Stem Cells - metabolism; human pluripotent stem cell; Humans; Mesoderm - cytology; Mesoderm - growth & development; Mesoderm - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Signal Transduction; T-Cell Acute Lymphocytic Leukemia Protein 1 - genetics; T-Cell Acute Lymphocytic Leukemia Protein 1 - metabolism; Transcription, Genetic; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; Wnt signaling
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.07.067

We analyzed chromatin dynamics and transcriptional activity of human embryonic stem cell (hESC)-derived cardiac progenitor cells (CPCs) and KDR+/CD34+ endothelial cells generated from different mesodermal origins. Using an unbiased algorithm to hierarchically rank genes modulated at the level of chromatin and transcription, we identified candidate regulators of mesodermal lineage determination. HOPX, a non-DNA-binding homeodomain protein, was identified as a candidate regulator of blood-forming endothelial cells. Using HOPX reporter and knockout hESCs, we show that HOPX regulates blood formation. Loss of HOPX does not impact endothelial fate specification but markedly reduces primitive hematopoiesis, acting at least in part through failure to suppress Wnt/β-catenin signaling. Thus, chromatin state analysis permits identification of regulators of mesodermal specification, including a conserved role for HOPX in governing primitive hematopoiesis. [Display omitted] •Chromatin dynamics reveal genes governing cell identity•HOPX is identified as a regulator of mesoderm lineage determination•HOPX modulates primitive hematopoiesis by inhibition of Wnt signaling Palpant et al. analyze gene expression and chromatin dynamics in cardiovascular progenitor cells derived from hPSCs to elucidate genes governing cell fate. HOPX is identified as a regulator of primitive hematopoiesis, providing insight into controlling cell lineages from pluripotency for disease modeling or therapeutic applications.