Dynamic HoxB4-regulatory Network During Embryonic Stem Cell Differentiation to Hematopoietic Cells

Blood. 2012 May 10;119(19):e139-47. doi: 10.1182/blood-2011-12-396754. Epub 2012 Mar 21.

Abstract

Efficient in vitro generation of hematopoietic stem cells (HSCs) from embryonic stem cells (ESCs) holds great promise for cell-based therapies to treat hematologic diseases. To date, HoxB4 remains the most effective transcription factor (TF) the overexpression of which in ESCs confers long-term repopulating ability to ESC-derived HSCs. Despite its importance, the components and dynamics of the HoxB4 transcriptional regulatory network is poorly understood, hindering efforts to develop more efficient protocols for in vitro derivation of HSCs. In the present study, we performed global gene-expression profiling and ChIP coupled with deep sequencing at 4 stages of the HoxB4-mediated ESC differentiation toward HSCs. Joint analyses of ChIP/deep sequencing and gene-expression profiling unveiled several global features of the HoxB4 regulatory network. First, it is highly dynamic and gradually expands during the differentiation process. Second, HoxB4 functions as a master regulator of hematopoiesis by regulating multiple hematopoietic TFs and chromatin-modification enzymes. Third, HoxB4 acts in different combinations with 4 other hematopoietic TFs (Fli1, Meis1, Runx1, and Scl) to regulate distinct sets of pathways. Finally, the results of our study suggest that down-regulation of mitochondria and lysosomal genes by HoxB4 plays a role in the impaired lymphoid lineage development from ESC-derived HSCs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blood Cells / metabolism
  • Blood Cells / physiology*
  • Cell Differentiation / genetics*
  • Cell Differentiation / physiology
  • Cell Lineage / genetics
  • Cell Lineage / physiology
  • Cells, Cultured
  • Embryonic Stem Cells / metabolism
  • Embryonic Stem Cells / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks / genetics*
  • Hematopoiesis / genetics*
  • Hematopoiesis / physiology
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Homeodomain Proteins / physiology*
  • Humans
  • Lymphocytes / metabolism
  • Lymphocytes / physiology
  • Mice
  • Microarray Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*

Substances

  • HOXB4 protein, human
  • Homeodomain Proteins
  • Transcription Factors