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Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):268-283
The epigenetic regulator RINF (CXXC5) maintains SMAD7 expression in human immature erythroid cells and sustains red blood cell expansion
Audrey Astori,1,2,3* Gabriel Matherat,1,2,3* Isabelle Munoz,1,2,3 Emilie-Fleur Gautier,1,2,3 Didier Surdez,3,4,5 Yaël Zermati,1,2 Frédérique Verdier,1,2 Sakina Zaidi,3,4,5 Vincent Feuillet,1 Amir Kadi,1 Evelyne Lauret,1,3 Olivier Delattre,3,4,5 Carine Lefèvre,1,2 Michaela Fontenay,1,2,6 Evelyne Ségal-Bendirdjian,7 Isabelle Dusanter-Fourt,1,3 Didier Bouscary,1,3 Olivier Hermine,2,3,8 Patrick Mayeux1,2,3 and Frédéric Pendino1,2,3
1Université de Paris, Institut Cochin, INSERM, CNRS; 2Laboratory of Excellence GR-ex; 3Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC); 4PSL Research University, Institut Curie Research Center, INSERM U830; 5SIREDO: Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Institut Curie; 6Service d'Hématologie Biologique, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Centre-Université de Paris; 7INSERM UMR-S 1124, Team: Cellular Homeostasis Cancer and Therapies, Université de Paris and 8Université de Paris, Institut Imagine, INSERM, CNRS, Paris, France.
*AA and GM contributed equally as co-first authors.
ABSTRACT
The gene CXXC5, encoding a retinoid-inducible nuclear factor (RINF), is located within a region at 5q31.2 commonly deleted in myelodysplastic syndrome and adult acute myeloid leukemia. RINF may act as an epigenetic regulator and has been proposed as a tumor suppressor in hematopoietic malignancies. However, functional studies in normal hematopoiesis are lacking, and its mechanism of action is unknown. Here, we evaluated the consequences of RINF silencing on cytokine-induced erythroid differentiation of human primary CD34+ progenitors. We found that RINF is expressed in immature erythroid cells and that RINF-knockdown accelerated erythropoietin-driven matura- tion, leading to a significant reduction (~45%) in the number of red blood cells, without affecting cell viability. The phenotype induced by RINF-silencing was dependent on tumor growth factor b (TGFb) and mediated by SMAD7, a TGFb-signaling inhibitor. RINF upregulates SMAD7 expression by direct binding to its promoter and we found a close correlation between RINF and SMAD7 mRNA levels both in CD34+ cells isolated from bone marrow of healthy donors and myelodysplastic syndrome patients with del(5q). Importantly, RINF knockdown attenu- ated SMAD7 expression in primary cells and ectopic SMAD7 expression was sufficient to prevent the RINF knockdown-dependent erythroid phenotype. Finally, RINF silencing affects 5’-hydroxymethylation of human erythroblasts, in agreement with its recently described role as a TET2-anchoring platform in mouse. Collectively, our data bring insight into how the epigenetic factor RINF, as a transcriptional regulator of SMAD7, may fine-tune cell sensitivity to TGFb superfamily cytokines and thus play an important role in both normal and pathological erythro- poiesis.
Introduction
In earlier work, we demonstrated that RINF loss-of-function affects granulopoiesis in normal and tumoral human hematopoietic cells.1 In keeping with its gene location at chromosome 5q31.2 (Online Supplementary Figure S1), a commonly deleted region associated with high risk in myeloid neoplasms,2 RINF loss of expression has been
Red Cell Biology & its Disorders
Correspondence:
FRÉDÉRIC PENDINO
frederic.pendino@inserm.fr
Received: June 18, 2020. Accepted: November 16, 2020. Pre-published: November 26, 2020.
https://doi.org/10.3324/haematol.2020.263558 ©2022 Ferrata Storti Foundation
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