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1.
Nucleic Acids Res ; 45(10): 5739-5756, 2017 Jun 02.
Article in English | MEDLINE | ID: mdl-28334849

ABSTRACT

Hypomorphic mutations in DNA-methyltransferase DNMT3B cause majority of the rare disorder Immunodeficiency, Centromere instability and Facial anomalies syndrome cases (ICF1). By unspecified mechanisms, mutant-DNMT3B interferes with lymphoid-specific pathways resulting in immune response defects. Interestingly, recent findings report that DNMT3B shapes intragenic CpG-methylation of highly-transcribed genes. However, how the DNMT3B-dependent epigenetic network modulates transcription and whether ICF1-specific mutations impair this process remains unknown. We performed a transcriptomic and epigenomic study in patient-derived B-cell lines to investigate the genome-scale effects of DNMT3B dysfunction. We highlighted that altered intragenic CpG-methylation impairs multiple aspects of transcriptional regulation, like alternative TSS usage, antisense transcription and exon splicing. These defects preferentially associate with changes of intragenic H3K4me3 and at lesser extent of H3K27me3 and H3K36me3. In addition, we highlighted a novel DNMT3B activity in modulating the self-regulatory circuit of sense-antisense pairs and the exon skipping during alternative splicing, through interacting with RNA molecules. Strikingly, altered transcription affects disease relevant genes, as for instance the memory-B cell marker CD27 and PTPRC genes, providing us with biological insights into the ICF1-syndrome pathogenesis. Our genome-scale approach sheds light on the mechanisms still poorly understood of the intragenic function of DNMT3B and DNA methylation in gene expression regulation.


Subject(s)
Alternative Splicing , Anorexia/genetics , Cachexia/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , Eye Abnormalities/genetics , Histones/genetics , Immunologic Deficiency Syndromes/genetics , Mutation , RNA, Messenger/genetics , Skin Diseases/genetics , Anorexia/immunology , Anorexia/pathology , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Cachexia/immunology , Cachexia/pathology , Cell Line, Transformed , CpG Islands , DNA (Cytosine-5-)-Methyltransferases/immunology , DNA Methylation , Epigenesis, Genetic , Eye Abnormalities/immunology , Eye Abnormalities/pathology , Facies , Female , Histones/immunology , Humans , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Immunologic Memory , Leukocyte Common Antigens/genetics , Leukocyte Common Antigens/immunology , Male , Promoter Regions, Genetic , RNA, Messenger/immunology , Skin Diseases/immunology , Skin Diseases/pathology , Transcription, Genetic , Tumor Necrosis Factor Receptor Superfamily, Member 7/genetics , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology , DNA Methyltransferase 3B
2.
Int J Neurosci ; 123(8): 587-90, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23509923

ABSTRACT

Joubert syndrome (JS) is a rare, complex autosomal recessive inherited disorder mostly characterized by partial or complete agenesis of the cerebellar vermis. There is a wide clinical and genetic heterogeneity in the syndrome. The main clinical features of JS are hypotonia, ataxia, developmental delay, oculomotor apraxia, breathing abnormalities and peculiar neuroimaging findings. A lot of additional features have been reported. Here, we first reported a case of the syndrome with natural killer (NK) cell deficiency. NK cell deficiency in JS might be not an incidental phenomenon. NK cell deficiency might be associated with JS when there are additional features such as recurrent infections and tumors. NK cell deficiency may be part of the clinical spectrum of JS. Reduced cellular immunity in association with NK cell deficiency may be a feature in a subset of JS patients, especially if there is a history of recurrent infections, tumors and autoimmune disorders.


Subject(s)
Cerebellar Diseases/complications , Cerebellar Diseases/immunology , Eye Abnormalities/complications , Eye Abnormalities/immunology , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/immunology , Kidney Diseases, Cystic/complications , Kidney Diseases, Cystic/immunology , Killer Cells, Natural/pathology , Retina/abnormalities , Abnormalities, Multiple , Cerebellum/abnormalities , Female , Humans , Immunologic Deficiency Syndromes/pathology , Infant , Lymphocyte Count , Retina/immunology
3.
Ann N Y Acad Sci ; 1274: 24-32, 2012 Dec.
Article in English | MEDLINE | ID: mdl-23252894

ABSTRACT

Presynaptic active zones are synaptic vesicle release sites that play essential roles in the function and pathology of mammalian neuromuscular junctions (NMJs). The molecular mechanisms of active zone organization use presynaptic voltage-dependent calcium channels (VDCCs) in NMJs as scaffolding proteins. VDCCs interact extracellularly with the muscle-derived synapse organizer, laminin ß2 and interact intracellularly with active zone-specific proteins, such as Bassoon, CAST/Erc2/ELKS2alpha, ELKS, Piccolo, and RIMs. These molecular mechanisms are supported by studies in P/Q- and N-type VDCCs double-knockout mice, and they are consistent with the pathological conditions of Lambert-Eaton myasthenic syndrome and Pierson syndrome, which are caused by autoantibodies against VDCCs or by a laminin ß2 mutation. During normal postnatal maturation, NMJs maintain the density of active zones, while NMJs triple their size. However, active zones become impaired during aging. Propitiously, muscle exercise ameliorates the active zone impairment in aged NMJs, which suggests the potential for therapeutic strategies.


Subject(s)
Aging/metabolism , Neuromuscular Junction/metabolism , Abnormalities, Multiple/immunology , Abnormalities, Multiple/metabolism , Animals , Autoantibodies/immunology , Calcium Channels/immunology , Calcium Channels/metabolism , Eye Abnormalities/immunology , Eye Abnormalities/metabolism , Humans , Lambert-Eaton Myasthenic Syndrome/immunology , Lambert-Eaton Myasthenic Syndrome/metabolism , Myasthenic Syndromes, Congenital , Nephrotic Syndrome/immunology , Nephrotic Syndrome/metabolism , Nerve Tissue Proteins/metabolism , Presynaptic Terminals/metabolism , Pupil Disorders/immunology , Pupil Disorders/metabolism
4.
J Immunol ; 189(8): 3957-69, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22966085

ABSTRACT

The lectin pathway of complement is an important component of innate immunity. Its activation has been thought to occur via recognition of pathogens by mannan-binding lectin (MBL) or ficolins in complex with MBL-associated serine protease (MASP)-2, followed by MASP-2 autoactivation and cleavage of C4 and C2 generating the C3 convertase. MASP-1 and MASP-3 are related proteases found in similar complexes. MASP-1 has been shown to aid MASP-2 convertase generation by auxiliary C2 cleavage. In mice, MASP-1 and MASP-3 have been reported to be central also to alternative pathway function through activation of profactor D and factor B. In this study, we present functional studies based on a patient harboring a nonsense mutation in the common part of the MASP1 gene and hence deficient in both MASP-1 and MASP-3. Surprisingly, we find that the alternative pathway in this patient functions normally, and is unaffected by reconstitution with MASP-1 and MASP-3. Conversely, we find that the patient has a nonfunctional lectin pathway, which can be restored by MASP-1, implying that this component is crucial for complement activation. We show that, although MASP-2 is able to autoactivate under artificial conditions, MASP-1 dramatically increases lectin pathway activity at physiological conditions through direct activation of MASP-2. We further demonstrate that MASP-1 and MASP-2 can associate in the same MBL complex, and that such cocomplexes are found in serum, providing a scenario for transactivation of MASP-2. Hence, in functional terms, it appears that MASP-1 and MASP-2 act in a manner analogous to that of C1r and C1s of the classical pathway.


Subject(s)
Abnormalities, Multiple/enzymology , Blepharoptosis/enzymology , Complement Pathway, Alternative/immunology , Complement Pathway, Mannose-Binding Lectin/immunology , Craniofacial Abnormalities/enzymology , Craniosynostoses/enzymology , Cryptorchidism/enzymology , Eye Abnormalities/enzymology , Heart Defects, Congenital/enzymology , Hip Dislocation, Congenital/enzymology , Mannose-Binding Protein-Associated Serine Proteases/physiology , Strabismus/enzymology , Abdominal Muscles/abnormalities , Abdominal Muscles/enzymology , Abdominal Muscles/immunology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/immunology , Animals , Blepharoptosis/genetics , Blepharoptosis/immunology , Codon, Nonsense , Complement Pathway, Alternative/genetics , Complement Pathway, Mannose-Binding Lectin/genetics , Craniofacial Abnormalities/genetics , Craniofacial Abnormalities/immunology , Craniosynostoses/genetics , Craniosynostoses/immunology , Cryptorchidism/genetics , Cryptorchidism/immunology , Developmental Disabilities/enzymology , Developmental Disabilities/genetics , Developmental Disabilities/immunology , Eye Abnormalities/genetics , Eye Abnormalities/immunology , Heart Defects, Congenital/genetics , Heart Defects, Congenital/immunology , Hip Dislocation, Congenital/genetics , Hip Dislocation, Congenital/immunology , Humans , Mannose-Binding Protein-Associated Serine Proteases/genetics , Strabismus/genetics , Strabismus/immunology , Transcriptional Activation/genetics , Transcriptional Activation/immunology
5.
J Reprod Immunol ; 45(1): 49-66, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10660262

ABSTRACT

Immune responses occurring between the embryo and mother have been shown to influence the embryo's tolerance to teratogens, including chemical teratogens and diabetes-induced teratogenic insult. In this study, we tried to evaluate whether maternal immunostimulation alters the embryo's response to heat shock, one of few teratogens which directly affect the embryo. In order to induce structural anomalies, both intact ICR female mice and mice which had been immunostimulated with xenogeneic rat splenocytes before mating, were exposed to two consecutive exposures to heat (43.6 +/- 0.2 degrees C) for 10 min on day 9 of pregnancy. The number of malformed fetuses, resorptions, and fetal weight were assessed on day 19 of pregnancy. Heat shock-induced apoptosis, and the level of heat shock protein (HSP) 60 expression, were examined in embryonic cells at different time points within 24 h after heating. All these indices differed dramatically in immunized and non-immunized heat shocked females. Heat shocked non-immunized females demonstrated an increased level of resorptions (approximately, 21% versus 8.6% in controls) and the proportion of fetuses with such anomalies as encephalocele and open eyes reached 28% and 21%, respectively. Maternal immunostimulation was associated with a significant decrease in the proportion of fetuses with encephalocele (12.8%), open eyes (8.9%), and resorptions (8%). The maximum level of heat shock-induced apoptosis in cell populations from the embryos of non-immunized females, was approximately, 30% versus 7% in cells of embryos of immunized mice. Heat shock was also followed by a significant increase in HSP60 expression, but only in the cells of embryos of non-immunized females. Together, these findings suggest that the tolerance of mouse embryos to a heat shock-induced teratogenic insult may, to some extent, depend on the character of the maternal immune responses.


Subject(s)
Congenital Abnormalities/etiology , Fetal Resorption/etiology , Fetus/immunology , Fever/immunology , Hot Temperature/adverse effects , Immunization , Pregnancy Complications/immunology , T-Lymphocytes/transplantation , Animals , Apoptosis , Chaperonin 60/analysis , Congenital Abnormalities/immunology , Congenital Abnormalities/prevention & control , Encephalocele/etiology , Encephalocele/immunology , Encephalocele/prevention & control , Eye Abnormalities/etiology , Eye Abnormalities/immunology , Eye Abnormalities/prevention & control , Female , Fetal Resorption/immunology , Fetal Resorption/prevention & control , Fetal Weight , Male , Mice , Mice, Inbred ICR , Pregnancy , Rats , Spleen/cytology
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