TY - JOUR
T1 - Polycombs and microRNA-223 regulate human granulopoiesis by transcriptional control of target gene expression
AU - Zardo, Giuseppe
AU - Ciolfi, Alberto
AU - Vian, Laura
AU - Starnes, Linda M.
AU - Billi, Monia
AU - Racanicchi, Serena
AU - Maresca, Carmen
AU - Fazi, Francesco
AU - Travaglini, Lorena
AU - Noguera, Nelida
AU - Mancini, Marco
AU - Nanni, Mauro
AU - Cimino, Giuseppe
AU - Lo-Coco, Francesco
AU - Grignani, Francesco
AU - Nervi, Clara
PY - 2012/4/19
Y1 - 2012/4/19
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2011-08-371344
DO - 10.1182/blood-2011-08-371344
M3 - Article
C2 - 22327224
AN - SCOPUS:84860319206
VL - 119
SP - 4034
EP - 4046
JO - Blood
JF - Blood
SN - 0006-4971
IS - 17
ER -