Nonredundant and locus-specific gene repression functions of PRC1 paralog family members in human hematopoietic stem/progenitor cells

Vincent van den Boom, Marjan Rozenveld-Geugien, Francesco Bonardi, Donatella Malanga, Djoke van Gosliga, Anne Margriet Heyink, Giuseppe Viglietto, Giovanni Morrone, Fabrizia Fusetti, Edo Vellenga, Jan Jacob Schuringa*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

37 Citations (Scopus)

Abstract

The Polycomb group (PcG) protein BMI1 is a key factor in regulating hematopoietic stem cell (HSC) and leukemic stem cell self-renewal and functions in the context of the Polycomb repressive complex 1 (PRC1). In humans, each of the 5 subunits of PRC1 has paralog family members of which many reside in PRC1 complexes, likely in a mutually exclusive manner, pointing toward a previously unanticipated complexity of Polycomb-mediated silencing. We used an RNA interference screening approach to test the functionality of these paralogs in human hematopoiesis. Our data demonstrate a lack of redundancy between various paralog family members, suggestive of functional diversification between PcG proteins. By using an in vivo biotinylation tagging approach followed by liquid chromatography-tandem mass spectrometry to identify PcG interaction partners, we confirmed the existence of multiple specific PRC1 complexes. We find that CBX2 is a nonredundant CBX paralog vital for HSC and progenitor function that directly regulates the expression of the cyclin-dependent kinase inhibitor p21, independently of BMI1 that dominantly controls expression of the INK4A/ARF locus. Taken together, our data show that different PRC1 paralog family members have nonredundant and locus-specific gene regulatory activities that are essential for human hematopoiesis.

Original languageEnglish
Pages (from-to)2452-2461
Number of pages10
JournalBlood
Volume121
Issue number13
DOIs
Publication statusPublished - 28-Mar-2013

Keywords

  • POLYCOMB GROUP PROTEINS
  • IMPAIRS SELF-RENEWAL
  • HUMAN CD34(+) CELLS
  • STEM-CELLS
  • HISTONE H2A
  • COMPLEX
  • BMI-1
  • CHROMATIN
  • H3
  • UBIQUITYLATION

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