Expression bias in retinoic acid responsive genes defines variations in neural differentiation of human pluripotent stem cells

Kavli Affiliate: Nenad Sestan

| Authors: Suel-Kee Kim, Seungmae Seo, Genevieve Stein-O’Brien, Amritha Jaishankar, Kazuya Ogawa, Nicola Micali, Victor Luria, Amir Karger, Yanhong Wang, Thomas M. Hyde, Joel E. Kleinman, Ty Voss, Elana J. Fertig, Joo-Heon Shin, Roland Bürli, Alan J. Cross, Nicholas J. Brandon, Daniel R. Weinberger, Joshua G. Chenoweth, Daniel J. Hoeppner, Nenad Sestan, Carlo Colantuoni and Ronald D. McKay

| Summary:

Variability between human pluripotent stem cell (hPSC) lines remains a challenge and opportunity in biomedicine. We identified differences in the early lineage emergence across hPSC lines that mapped on the antero-posterior axis of embryonic development. RNA-seq analysis revealed dynamic transcriptomic patterns that defined the emergence of mesendodermal versus neuroectodermal lineages conserved across hPSC lines and cell line-specific transcriptional signatures that were invariant across differentiation. The stable cell line-specific transcriptomic patterns predicted the retinoic acid (RA) response of the cell lines, resulting in distinct bias towards fore-versus hind-brain fates. Replicate hPSC lines and paired adult donor tissue demonstrated that cells from individual humans expressed unique and long-lasting transcriptomic signatures associated with evolutionarily recent genes. In addition to this genetic contribution, we found that replicate lines from a single donor showed divergent brain regional fates linked to distinct chromatin states, indicating that epigenetic mechanisms also contribute to neural fate differences. This variation in lineage bias and its correlation with RA responsive gene expression was also observed in a large collection of hPSC lines. These results define transcriptomic differences in hPSCs that initiate a critical early step specifying anterior or posterior neural fates.

Read More