The Experts below are selected from a list of 930 Experts worldwide ranked by ideXlab platform
Amanda J Whipple - One of the best experts on this subject based on the ideXlab platform.
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imprinted maternally expressed micrornas antagonize paternally driven gene programs in neurons
Molecular Cell, 2020Co-Authors: Amanda J Whipple, Vincent Bretonprovencher, Hannah N Jacobs, Udbhav K Chitta, Phillip A SharpAbstract:Summary Imprinted genes with parental-biased allelic expression are frequently co-regulated and enriched in common biological pathways. Here, we functionally characterize a large cluster of microRNAs (miRNAs) expressed from the maternally inherited allele (“maternally expressed”) to explore the molecular and cellular consequences of imprinted miRNA activity. Using an induced neuron (iN) culture system, we show that maternally expressed miRNAs from the miR-379/410 cluster direct the RNA-induced silencing complex (RISC) to transcriptional and developmental regulators, including paternally expressed transcripts like PLAGL1. Maternal deletion of this imprinted miRNA cluster resulted in increased protein levels of several targets and upregulation of a broader transcriptional program regulating synaptic transmission and neuronal function. A subset of the transcriptional changes resulting from miR-379/410 deletion can be attributed to de-repression of PLAGL1. These data suggest maternally expressed miRNAs antagonize paternally driven gene programs in neurons.
Dietmar Spengler - One of the best experts on this subject based on the ideXlab platform.
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D (2012) Transient neonatal diabetes mellitus gene Zac1 impairs insulin secretion
2016Co-Authors: Anke Hoffmann, Dietmar SpenglerAbstract:The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies60 % of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1misexpression in pancreatic cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/PLAGL1 target gene in murine cells. Doubling Zac1 expression reduced Rasgrf1 expression, the stimulus-induced activation of mitogen-activated protein ki-nase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and, ultimately, insulin secretion. Normalizing Rasgrf1 expres-sion reversed this phenotype. Moreover, the transplantation of Zac1-overexpressing cells failed to reinstate euglycemia in ex-perimental diabetic mice. In contrast, Zac1 expression did not interfere with the signaling of the glucagon-like peptide 1 receptor (GLP-1R), and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy. Transient neonatal diabetes mellitus (TNDM) due to chromo-some 6q anomalies is a rare cause of early-onset hyperglycemia in term newborn infants (1). Neonates typically present with low birth weight and high blood glucose values, features of low pan-creatic insulin secretion in utero and after delivery. Initially insulin treatment is required, whereas by 3 months insulin secretion has improved to allow its discontinuation. Patients remain in appar
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transient neonatal diabetes mellitus gene zac1 impairs insulin secretion in mice through rasgrf1
Molecular and Cellular Biology, 2012Co-Authors: Anke Hoffmann, Dietmar SpenglerAbstract:The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies ≈ 60% of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1 misexpression in pancreatic β cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/PLAGL1 target gene in murine β cells. Doubling Zac1 expression reduced Rasgrf1 expression, the stimulus-induced activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and, ultimately, insulin secretion. Normalizing Rasgrf1 expression reversed this phenotype. Moreover, the transplantation of Zac1-overexpressing β cells failed to reinstate euglycemia in experimental diabetic mice. In contrast, Zac1 expression did not interfere with the signaling of the glucagon-like peptide 1 receptor (GLP-1R), and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy.
Phillip A Sharp - One of the best experts on this subject based on the ideXlab platform.
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imprinted maternally expressed micrornas antagonize paternally driven gene programs in neurons
Molecular Cell, 2020Co-Authors: Amanda J Whipple, Vincent Bretonprovencher, Hannah N Jacobs, Udbhav K Chitta, Phillip A SharpAbstract:Summary Imprinted genes with parental-biased allelic expression are frequently co-regulated and enriched in common biological pathways. Here, we functionally characterize a large cluster of microRNAs (miRNAs) expressed from the maternally inherited allele (“maternally expressed”) to explore the molecular and cellular consequences of imprinted miRNA activity. Using an induced neuron (iN) culture system, we show that maternally expressed miRNAs from the miR-379/410 cluster direct the RNA-induced silencing complex (RISC) to transcriptional and developmental regulators, including paternally expressed transcripts like PLAGL1. Maternal deletion of this imprinted miRNA cluster resulted in increased protein levels of several targets and upregulation of a broader transcriptional program regulating synaptic transmission and neuronal function. A subset of the transcriptional changes resulting from miR-379/410 deletion can be attributed to de-repression of PLAGL1. These data suggest maternally expressed miRNAs antagonize paternally driven gene programs in neurons.
I. Karen Temple - One of the best experts on this subject based on the ideXlab platform.
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Clinical utility gene card for: Transient Neonatal Diabetes Mellitus, 6q24-related
European Journal of Human Genetics, 2014Co-Authors: Deborah J.g. Mackay, Guiomar Perez De Nanclares, Reiner Siebert, Susanne Bens, I. Karen TempleAbstract:aOwing to very small patient numbers, the precise percentages of different molecular aetiologies differ slightly as the sizes of patient cohorts increase. b490% of paternal uniparental disomy in 6q24 TNDM is whole-chromosome isodisomy; however, segmental UPD and heterodisomy are also seen. Maternal uniparental disomy of chromosome 6 is not associated with 6q24 TNDM. cPaternally inherited duplications of varying sizes have been identified in 6q24 TNDM, but as all contain PLAGL1, they are here designated PLAGL1 duplications. Maternally inherited duplications of PLAGL1 are not associated with 6q24 TNDM. d60% of cases with PLAGL1 hypomethylation have Multilocus Methylation Defect, that is, defects in imprinted DNA methylation at multiple imprinted loci (MLMD). Of these, approximately half have homozygous mutation of ZFP573 (a mutation database exists for ZFP57: www.lovd.nl/ ZFP57). PLAGL1 hypomethylation may also be part of MLMD associated with rare mutations in NLRP2 (NM_001174081), NLRP7 (NM_001127255) and KHDC3L (NM_001017361), but individuals affected by such syndromes may not present with 6q24 TNDM.
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Transient neonatal diabetes mellitus type 1
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2010Co-Authors: Deborah J.g. Mackay, I. Karen TempleAbstract:Transient neonatal diabetes mellitus type 1 (TNDM1) is a rare but remarkable form of diabetes which presents in infancy, resolves in the first months of life, but then frequently recurs in later life. It is caused by overexpression of the imprinted genes PLAGL1 and HYMAI on human chromosome 6q24. The expression of these genes is normally restricted to the paternal allele as a result of maternal DNA methylation. TNDM1 is not associated with mutation of PLAGL1 or HYMAI, but rather with their overexpression via uniparental disomy, chromosome duplication, or relaxation of imprinting. Study of patients with TNDM1 has provided valuable insights into the causes of imprinting disorders. Over half of patients with maternal hypomethylation at the TNDM1 locus have additional hypomethylation of other maternally methylated imprinted genes throughout the genome, and the majority of these patients have mutations in the transcription factor ZFP57. TNDM1 with maternal hypomethylation has also been observed in patients conceived by assisted reproduction, and in discordant monozygotic twins. The variable clinical features of TNDM1 may be associated with variation in the nature of the underlying epigenetic and genetic mutations, and future study of this disorder is likely to yield further insights not only into the biological mechanisms of imprinting, but also into the contribution of epigenetics to diabetes.
Anke Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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D (2012) Transient neonatal diabetes mellitus gene Zac1 impairs insulin secretion
2016Co-Authors: Anke Hoffmann, Dietmar SpenglerAbstract:The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies60 % of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1misexpression in pancreatic cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/PLAGL1 target gene in murine cells. Doubling Zac1 expression reduced Rasgrf1 expression, the stimulus-induced activation of mitogen-activated protein ki-nase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and, ultimately, insulin secretion. Normalizing Rasgrf1 expres-sion reversed this phenotype. Moreover, the transplantation of Zac1-overexpressing cells failed to reinstate euglycemia in ex-perimental diabetic mice. In contrast, Zac1 expression did not interfere with the signaling of the glucagon-like peptide 1 receptor (GLP-1R), and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy. Transient neonatal diabetes mellitus (TNDM) due to chromo-some 6q anomalies is a rare cause of early-onset hyperglycemia in term newborn infants (1). Neonates typically present with low birth weight and high blood glucose values, features of low pan-creatic insulin secretion in utero and after delivery. Initially insulin treatment is required, whereas by 3 months insulin secretion has improved to allow its discontinuation. Patients remain in appar
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transient neonatal diabetes mellitus gene zac1 impairs insulin secretion in mice through rasgrf1
Molecular and Cellular Biology, 2012Co-Authors: Anke Hoffmann, Dietmar SpenglerAbstract:The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies ≈ 60% of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1 misexpression in pancreatic β cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/PLAGL1 target gene in murine β cells. Doubling Zac1 expression reduced Rasgrf1 expression, the stimulus-induced activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, and, ultimately, insulin secretion. Normalizing Rasgrf1 expression reversed this phenotype. Moreover, the transplantation of Zac1-overexpressing β cells failed to reinstate euglycemia in experimental diabetic mice. In contrast, Zac1 expression did not interfere with the signaling of the glucagon-like peptide 1 receptor (GLP-1R), and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy.