02803nas a2200625   4500000000100000000000100001008004100002260001500043653002500058653001400083653001700097653002400114653004600138653001100184653002700195653001000222653001800232653001400250653001900264653003900283653002400322653001700346653002100363653002700384653001300411100001700424700001700441700002800458700002300486700001700509700001800526700001700544700001600561700001700577700001500594700001900609700002100628700001200649700002000661700001800681700001800699700001800717700002400735700002500759700002400784700002300808700001700831700002100848700002000869245011400889300001401003490000701017520113901024022001402163       2024                            d  c2024-09-1010aCell Differentiation10aCell Line10aCell Lineage10aEpigenesis, Genetic10aGene Expression Regulation, Developmental10aHumans10aPluripotent Stem Cells10aSOX2110aTranscriptome10aTretinoin10aacid signaling10aanterior or posterior neural fates10acell line variation10aearly embryo10ahuman population10aPluripotent Stem Cells10aretinoic1 aSuel-Kee Kim1 aSeungmae Seo1 aGenevieve Stein-O'Brien1 aAmritha Jaishankar1 aKazuya Ogawa1 aNicola Micali1 aVictor Luria1 aAmir Karger1 aYanhong Wang1 aHyojin Kim1 aThomas M. Hyde1 aJoel E. Kleinman1 aTy Voss1 aElana J. Fertig1 aJoo-Heon Shin1 aRoland Bürli1 aAlan J. Cross1 aNicholas J. Brandon1 aDaniel R. Weinberger1 aJoshua G. Chenoweth1 aDaniel J. Hoeppner1 aNenad Sestan1 aCarlo Colantuoni1 aRonald D. McKay00aIndividual variation in the emergence of anterior-to-posterior neural fates from human pluripotent stem cells  a1336-13500 v193 aVariability between human pluripotent stem cell (hPSC) lines remains a challenge and opportunity in biomedicine. In this study, hPSC lines from multiple donors were differentiated toward neuroectoderm and mesendoderm lineages. We revealed dynamic transcriptomic patterns that delineate the emergence of these lineages, which were conserved across lines, along with individual line-specific transcriptional signatures that were invariant throughout differentiation. These transcriptomic signatures predicted an antagonism between SOX21-driven forebrain fates and retinoic acid-induced hindbrain fates. Replicate lines and paired adult tissue demonstrated the stability of these line-specific transcriptomic traits. We show that this transcriptomic variation in lineage bias had both genetic and epigenetic origins, aligned with the anterior-to-posterior structure of early mammalian development, and was present across a large collection of hPSC lines. These findings contribute to developing systematic analyses of PSCs to define the origin and consequences of variation in the early events orchestrating individual human development.  a2213-6711