Polycombs and microRNA-223 regulate human granulopoiesis by transcriptional control of target gene expression

Giuseppe Zardo, Alberto Ciolfi, Laura Vian, Linda M. Starnes, Monia Billi, Serena Racanicchi, Carmen Maresca, Francesco Fazi, Lorena Travaglini, Nelida Noguera, Marco Mancini, Mauro Nanni, Giuseppe Cimino, Francesco Lo-Coco, Francesco Grignani, Clara Nervi

Research output: Contribution to journalArticlepeer-review

Abstract

Epigenetic modifications regulate developmental genes involved in stem cell identity and lineage choice. NFI-A is a post transcriptional microRNA-223 (miR-223) target directing human hematopoietic progenitor lineage decision: NFI-A induction or silencing boosts erythropoiesis or granulopoiesis, respectively. Here we show that NFI-A promoter silencing, which allows granulopoiesis, is guaranteed by epigenetic events, including the resolution of opposing chromatin "bivalent domains," hypermethylation, recruitment of polycomb (PcG)-RNAi complexes, and miR-223 promoter targeting activity. During granulopoiesis, miR-223 localizes inside the nucleus and targets the NFI-A promoter region containing PcGs binding sites and miR-223 complementary DNA sequences, evolutionarily conserved in mammalians. Remarkably, both the integrity of the PcGs-RNAi complex and DNA sequences matching the seed region of miR-223 are required to induce NFI-A transcriptional silencing. Moreover, ectopic miR-223 expression in human myeloid progenitors causes heterochromatic repression of NFI-A gene and channels granulopoiesis, whereas its stable knockdown produces the opposite effects. Our findings indicate that, besides the regulation of translation of mRNA targets, endogenous miRs can affect gene expression at the transcriptional level, functioning in a critical interface between chromatin remodeling complexes and the genome to direct fate lineage determination of hematopoietic progenitors.

Original languageEnglish
Pages (from-to)4034-4046
Number of pages13
JournalBlood
Volume119
Issue number17
DOIs
Publication statusPublished - Apr 19 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Fingerprint Dive into the research topics of 'Polycombs and microRNA-223 regulate human granulopoiesis by transcriptional control of target gene expression'. Together they form a unique fingerprint.

Cite this