First name
Mahshid
Last name
Rahmat
Year of Study
Thesis Title
Functional dissection of the histone demethylase Jmjd3 in B cell lymphopoiesis
Thesis Abstract
Histone H3 lysine-27 trimethylation (H3K27me3) is an epigenetic mark that exerts a critical role in heritable gene repression. Modulation of H3K27me3
levels influence cell proliferation, survival and differentiation. In mammalian cells, the Jumonji-C containing proteins JMJD3/KDM6B and UTX/KDM6A are the only known enzymes involved in H3K27me3 demethylation. Jmjd3 has been previously shown to play an important role in mediating macrophage
driven inflammatory responses and in in regulating somatic cell reprogramming and cellular senescence. To study the role of JMJD3 in B lymphocyte development and activation, I generated Jmjd3 conditional knock-out mice (JMJD3fl). Analysis of B cellspecific Jmjd3 KO mice revealed that Jmjd3 regulates the size of the B cell progenitor pool acting primarily on the pre-B cell compartment. Jmjd3 deficient animals showed also an increase in the fraction of splenic marginal zone B cells that was associated to a reduction in peritoneal cavity B-1a B cells. In vivo BrdU labeling assays suggested a longer lifespan of Jmjd3 mutant mature B cells, which was not dependent on improved cell survival. In vitro stimulation assays revealed a selective defect of Jmjd3 mutant B cells to proliferate in response to the TLR4 ligand LPS, which was alleviated by IL- 4 co-stimulation. Jmjd3 was critical to drive the first one-to-two cell divisions following LPS stimulation suggesting a critical role in the initial activation of the resting B cells. RNA sequencing data, revealed a comprehensive control exerted by Jmjd3 on the expression of a substantial number of cell-cycle regulated genes including those cyclins, CDK inhibitors and factors involved in DNA replication and mitosis. Regulation of gene expression mediated by Jmjd3 was not associated with measurable changes in global H3K27me3 levels. All together these results identify Jmjd3 as an important regulator of B cell lymphopoiesis and a selective effector of B cell innate immune responses.
levels influence cell proliferation, survival and differentiation. In mammalian cells, the Jumonji-C containing proteins JMJD3/KDM6B and UTX/KDM6A are the only known enzymes involved in H3K27me3 demethylation. Jmjd3 has been previously shown to play an important role in mediating macrophage
driven inflammatory responses and in in regulating somatic cell reprogramming and cellular senescence. To study the role of JMJD3 in B lymphocyte development and activation, I generated Jmjd3 conditional knock-out mice (JMJD3fl). Analysis of B cellspecific Jmjd3 KO mice revealed that Jmjd3 regulates the size of the B cell progenitor pool acting primarily on the pre-B cell compartment. Jmjd3 deficient animals showed also an increase in the fraction of splenic marginal zone B cells that was associated to a reduction in peritoneal cavity B-1a B cells. In vivo BrdU labeling assays suggested a longer lifespan of Jmjd3 mutant mature B cells, which was not dependent on improved cell survival. In vitro stimulation assays revealed a selective defect of Jmjd3 mutant B cells to proliferate in response to the TLR4 ligand LPS, which was alleviated by IL- 4 co-stimulation. Jmjd3 was critical to drive the first one-to-two cell divisions following LPS stimulation suggesting a critical role in the initial activation of the resting B cells. RNA sequencing data, revealed a comprehensive control exerted by Jmjd3 on the expression of a substantial number of cell-cycle regulated genes including those cyclins, CDK inhibitors and factors involved in DNA replication and mitosis. Regulation of gene expression mediated by Jmjd3 was not associated with measurable changes in global H3K27me3 levels. All together these results identify Jmjd3 as an important regulator of B cell lymphopoiesis and a selective effector of B cell innate immune responses.
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