Age-Associated Decrease of the Histone Methyltransferase SUV39H1 in HSC Perturbs Heterochromatin and B Lymphoid Differentiation.
The capacity of hematopoietic stem cells (HSC) to generate B lymphocytes declines with age, contributing to impaired immune function in the elderly. Here we show that the histone methyltransferase SUV39H1 plays an important role in human B lymphoid differentiation and that expression of SUV39H1 decreases with age in both human and mouse HSC, leading to a global reduction in H3K9 trimethylation and perturbed heterochromatin function. Further, we demonstrate that SUV39H1 is a target of microRNA miR-125b, a known regulator of HSC function, and that expression of miR-125b increases with age in human HSC. Overexpression of miR-125b and inhibition of SUV39H1 in young HSC induced loss of B cell potential. Conversely, both inhibition of miR-125 and enforced expression of SUV39H1 improved the capacity of HSC from elderly individuals to generate B cells. Our findings highlight the importance of heterochromatin regulation in HSC aging and B lymphopoiesis.
INSERM UMRS-1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
Dounia
D
Djeghloul
INSERM UMRS-1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
Klaudia
K
Kuranda
INSERM UMRS-1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
Isabelle
I
Kuzniak
INSERM UMRS-1170, Gustave Roussy Cancer Campus, Université Paris Sud - Université Paris-Saclay, Villejuif, France.
Daniela
D
Barbieri
INSERM UMRS-967, Institut de Radiobiologie Cellulaire et Moléculaire, Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France.
Irina
I
Naguibneva
INSERM UMRS-1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
Caroline
C
Choisy
INSERM UMRS-1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
Jean-Christophe
JC
Bories
INSERM UMRS-1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
Christine
C
Dosquet
INSERM UMRS-1131, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
Marika
M
Pla
AP-HP Unité de Thérapie Cellulaire, Centre d'Investigation Clinique en Biothérapie Cellulaire and INSERM UMRS-1160, Université Paris Diderot, Paris, France.
Valérie
V
Vanneaux
AP-HP Hematology Transplantation and INSERM UMRS-1160, Université Paris Diderot, Paris, France.
Gérard
G
Socié
INSERM UMRS-1170, Gustave Roussy Cancer Campus, Université Paris Sud - Université Paris-Saclay, Villejuif, France.
Françoise
F
Porteu
INSERM UMRS-1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
David
D
Garrick
INSERM UMRS-1126, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France. Electronic address: michele.goodhardt@univ-paris-diderot.fr.
Michele
M
Goodhardt
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000070416:Antagomirs / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D001483:Base Sequence; D002454:Cell Differentiation; D005260:Female; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology*; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000276:immunology; D051379:Mice; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D061251:Primary Cell Culture; D012097:Repressor Proteins / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction
D000070416:Antagomirs; D006570:Heterochromatin; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C407843:SUV39H1 protein, human; D008780:Methyltransferases