Laser Capture and Deep Sequencing Reveals the Transcriptomic Programmes Regulating the Onset of Pancreas and Liver Differentiation in Human Embryos

Rachel E. Jennings, Andrew A. Berry, David T. Gerrard, Stephen J. Wearne, James Strutt, Sarah Withey, Mariya Chhatriwala, Karen Piper Hanley, Ludovic Vallier, Nicoletta Bobola, Neil A. Hanley*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

To interrogate the alternative fates of pancreas and liver in the earliest stages of human organogenesis, we developed laser capture, RNA amplification, and computational analysis of deep sequencing. Pancreas-enriched gene expression was less conserved between human and mouse than for liver. The dorsal pancreatic bud was enriched for components of Notch, Wnt, BMP, and FGF signaling, almost all genes known to cause pancreatic agenesis or hypoplasia, and over 30 unexplored transcription factors. SOX9 and RORA were imputed as key regulators in pancreas compared with EP300, HNF4A, and FOXA family members in liver. Analyses implied that current in vitro human stem cell differentiation follows a dorsal rather than a ventral pancreatic program and pointed to additional factors for hepatic differentiation. In summary, we provide the transcriptional codes regulating the start of human liver and pancreas development to facilitate stem cell research and clinical interpretation without inter-species extrapolation. Jennings et al. present the first transcriptomes at the inception of liver and pancreas development in very early post-implantation human embryos. By computational analysis, they impute regulatory signatures in each organ, including new transcription factors in pancreas and new guidance for human pluripotent stem cell differentiation.

Original languageEnglish
Pages (from-to)1387-1394
Number of pages8
JournalStem Cell Reports
Volume9
Issue number5
DOIs
Publication statusPublished - 14 Nov 2017

Bibliographical note

Funding Information:
We are very grateful to all women who consented to take part in our research program and for the assistance of research nurses and clinical colleagues at Manchester University NHS Foundation Trust. This project received support from the UK Medical Research Council (MRC) (R.E.J. was a clinical research training fellow; additional funding from MR/L009986/1 to N.B. and N.A.H.; and MR/J003352/1 to K.P.H.), the Academy of Medical Sciences (supported by Wellcome Trust, MRC, British Heart Foundation , Arthritis Research UK , the Royal College of Physicians and Diabetes UK ) (R.E.J.), the Society for Endocrinology (R.E.J.), the Wellcome Trust (N.A.H. was a senior fellow in clinical science, 088566 ; additional support from grant 105610/Z/14/Z ), and the British Council and JDRF ( 14BX15NHBG to N.A.H.).

Publisher Copyright:
© 2017 The Authors

Keywords

  • development
  • embryo
  • human
  • liver
  • pancreas
  • RNA sequencing
  • stem cell
  • transcriptome

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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