MKRN3 inhibits the reproductive axis through actions in kisspeptin-expressing neurons.

Published on Aug 3, 2020in Journal of Clinical Investigation14.808
· DOI :10.1172/JCI136564
Ana Paula Abreu20
Estimated H-index: 20
(Brigham and Women's Hospital),
Carlos A. Toro14
Estimated H-index: 14
(Oregon National Primate Research Center)
+ 11 AuthorsUrsula B. Kaiser71
Estimated H-index: 71
(Brigham and Women's Hospital)
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Abstract
: The identification of loss-of-function mutations in MKRN3 in patients with central precocious puberty (CPP) in association with the decrease in MKRN3 expression in the medial basal hypothalamus (MBH) of mice prior to the initiation of reproductive maturation suggest that MKRN3 is acting as a 'brake' on GnRH secretion during childhood. In the current study, we investigated the mechanism by which MKRN3 prevents premature manifestation of the pubertal process. We showed that, as in mice, MKRN3 expression is high in the hypothalamus of rats and nonhuman primates early in life, declining as puberty approaches, and is independent of sex steroid hormones. We demonstrated that Mkrn3 is expressed in Kiss1 neurons of the mouse hypothalamic arcuate nucleus (ARC) and that MKRN3 repressed promoter activity of human KISS1 and TAC3, two key stimulators of GnRH secretion. We further showed that MKRN3 has ubiquitinase activity, that this activity is reduced by MKRN3 mutations affecting the RING finger domain, and that these mutations compromised the ability of MKRN3 to repress KISS1 and TAC3 promoter activity. These results indicate that MKRN3 acts to prevent puberty initiation, at least in part, by repressing KISS1 and TAC3 transcription and that this action may involve a MKRN3-directed ubiquitination-mediated mechanism.
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4 Authors (Eui Beom Jeong, ..., Eun Young Kim)
References64
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#1Simone Tamburri (IEO: European Institute of Oncology)H-Index: 5
#2Elisa Lavarone (IEO: European Institute of Oncology)H-Index: 4
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Summary Polycomb group proteins (PcGs) maintain transcriptional repression to preserve cellular identity in two distinct repressive complexes, PRC1 and PRC2, that modify histones by depositing H2AK119ub1 and H3K27me3, respectively. PRC1 and PRC2 exist in different variants and show a complex regulatory cross-talk. However, the contribution that H2AK119ub1 plays in mediating PcG repressive functions remains largely controversial. Using a fully catalytic inactive RING1B mutant, we demonstrated tha...
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#1Violeta Heras (UCO: University of Córdoba (Spain))H-Index: 10
#2Susana Sangiao-Alvarellos (University of A Coruña)H-Index: 28
Last. Ana Paula Abreu (Brigham and Women's Hospital)H-Index: 20
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Mkrn3, the maternally imprinted gene encoding the makorin RING-finger protein-3, has recently emerged as putative pubertal repressor, as evidenced by central precocity caused by MKRN3 mutations in humans; yet, the molecular underpinnings of this key regulatory action remain largely unexplored. We report herein that the microRNA, miR-30, with three binding sites in a highly conserved region of its 3′ UTR, operates as repressor of Mkrn3 to control pubertal onset. Hypothalamic miR-30b expression in...
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#1Alessandra Mancini (QMUL: Queen Mary University of London)H-Index: 4
#2Sasha Howard (QMUL: Queen Mary University of London)H-Index: 12
Last. Leo Dunkel (QMUL: Queen Mary University of London)H-Index: 70
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This is a pre-copyedited, author-produced version of an article accepted for publication in Human Molecular Genetics following peer review. The version of record Mancini, A., et al. (2019). "EAP1 regulation of GnRH promoter activity is important for human pubertal timing." is available online at: https://doi.org/10.1093/hmg/ddy451
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#1Luciana Pinto Valadares (UnB: University of Brasília)H-Index: 3
#2Cinthia Gabriel Meireles (UnB: University of Brasília)H-Index: 2
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: MKRN3 mutations represent the most common genetic cause of central precocious puberty (CPP) but associations between genotype and clinical features have not been extensively explored. This systematic review and meta-analysis investigated genotype-phenotype associations and prevalence of MKRN3 mutations in CPP. The search was conducted in seven electronic databases (Cochrane, EMBASE, LILACS, LIVIVO, PubMed, Scopus, and Web of Science) for articles published until 4 September 2018. Studies evalu...
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AMP-activated protein kinase (AMPK) plays a key role in controlling energy metabolism in response to physiological and nutritional status. Although AMPK activation has been proposed as a promising molecular target for treating obesity and its related comorbidities, the use of pharmacological AMPK activators has been met with contradictory therapeutic challenges. Here we show a regulatory mechanism for AMPK through its ubiquitination and degradation by the E3 ubiquitin ligase makorin ring finger ...
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#1Carlos A. Toro (Oregon National Primate Research Center)H-Index: 14
#2Hollis Wright (Oregon National Primate Research Center)H-Index: 7
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Polycomb group (PcG) proteins control the timing of puberty by repressing the Kiss1 gene in hypothalamic arcuate nucleus (ARC) neurons. Here we identify two members of the Trithorax group (TrxG) of modifiers, mixed-lineage leukemia 1 (MLL1), and 3 (MLL3), as central components of an activating epigenetic machinery that dynamically counteracts PcG repression. Preceding puberty, MLL1 changes the chromatin configuration at the promoters of Kiss1 and Tac3, two genes required for puberty to occur, fr...
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#1Jian Qiu (OHSU: Oregon Health & Science University)H-Index: 30
#2Casey C Nestor (OHSU: Oregon Health & Science University)H-Index: 8
Last. Oline K. Rønnekleiv (Oregon National Primate Research Center)H-Index: 68
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Puberty and fertility are necessary for survival of the species. An evolutionarily ancient region of the brain called the hypothalamus regulates these processes. The hypothalamus releases a chemical messenger called gonadotropin-releasing hormone (or GnRH for short), which is then transported from the brain to the pituitary gland. GnRH activates the pituitary gland, which in turn releases reproductive hormones that control ovulation in females and sperm production in males. For this process to w...
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#1Ana Paula Abreu (Brigham and Women's Hospital)H-Index: 20
#2Ursula B. Kaiser (Brigham and Women's Hospital)H-Index: 71
Summary Puberty marks the end of childhood and is a period when individuals undergo physiological and psychological changes to achieve sexual maturation and fertility. The hypothalamic-pituitary-gonadal axis controls puberty and reproduction and is tightly regulated by a complex network of excitatory and inhibitory factors. This axis is active in the embryonic and early postnatal stages of life and is subsequently restrained during childhood, and its reactivation culminates in puberty initiation...
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#1Alejandro Lomniczi (Oregon National Primate Research Center)H-Index: 32
#2Hollis Wright (Oregon National Primate Research Center)H-Index: 7
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In primates, puberty is unleashed by increased GnRH release from the hypothalamus following an interval of juvenile quiescence. GWAS implicates Zinc finger (ZNF) genes in timing human puberty. Here we show that hypothalamic expression of several ZNFs decreased in agonadal male monkeys in association with the pubertal reactivation of gonadotropin secretion. Expression of two of these ZNFs, GATAD1 and ZNF573, also decreases in peripubertal female monkeys. However, only GATAD1 abundance increases w...
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#2Delanie B Macedo (Brigham and Women's Hospital)H-Index: 3
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Pubertal timing is influenced by complex interactions among genetic, nutritional, environmental, and socioeconomic factors. The role of MKRN3, an imprinted gene located in the Prader–Willi syndrome critical region (chromosome 15q11–13), in pubertal initiation was first described in 2013 after the identification of deleterious MKRN3 mutations in five families with central precocious puberty (CPP) using whole-exome sequencing analysis. Since then, additional loss-of-function mutations of MKRN3 hav...
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Reproduction is an essential function for perpetuation of the species. As such, it is controlled by sophisticated regulatory mechanisms that allow a perfect match between environmental conditions and internal cues to ensure adequate pubertal maturation and achievement of reproductive capacity. Besides classical genetic regulatory events, mounting evidence has documented that different epigenetic mechanisms operate at different levels of the reproductive axis to finely tune the development and fu...
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Background null Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common types of cancer that cause a substantial number of cancer-related deaths. Our previous study has revealed that makorin ring finger protein 3 (MKRN3) may act as a key regulator of the SCCHN tumorigenesis; however, its specific role in SCCHN progression has not been reported. null Methods null The Cancer Genome Atlas (TCGA) data analysis and quantitative polymerase chain reaction (qPCR) were used to quan...
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#2Pavlos Fanis (The Cyprus Institute of Neurology and Genetics)H-Index: 9
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Background Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1 and KISS1R genes were investigated in patients with CPP. Methods Fifty-four index girls and 2 index boys with CPP were first tested by Sanger sequencing fo...
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#2Delphine Franssen (University of Liège)H-Index: 12
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Sexual maturation in humans is characterized by a unique individual variability. Pubertal onset is a highly heritable polygenic trait but it is also affected by environmental factors such as obesity or endocrine disrupting chemicals. The last 30 years have been marked by a constant secular trend toward earlier age at onset of puberty in girls and boys around the world. More recent data, although more disputed, suggest an increased incidence in idiopathic central precocious puberty. Such trends p...
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Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non-small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor gr...
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Background Paternally inherited loss-of-function mutations in MKRN3 underlie central precocious puberty (CPP). We describe clinical and genetic features of CPP patients with paternally inherited MKRN3 mutations in two independent families. Methods The single coding exon of MKRN3 was analyzed in three patients with CPP and their family members, followed by segregation analyses. Additionally, we report the patients' responses to GnRH analog treatment. Results A paternally inherited novel heterozyg...
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#2Mauro S. B. Silva (university of lille)H-Index: 2
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Abstract Gonadotropin-releasing hormone (GnRH) is the master regulator of the hypothalamic-pituitary-gonadal (HPG) axis, and therefore of fertility and reproduction. The release pattern of GnRH by the hypothalamus includes both pulses and surges. However, despite a considerable body of evidence in support of a determinant role for kisspeptin, the mechanisms regulating a GnRH pulse and surge remain a topic of debate. In this review we challenge the view of kisspeptin as an absolute “monarch”, and...
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Prader-Willi Syndrome (PWS) is a rare and incurable congenital neurodevelopmental disorder, resulting from the absence of expression of a group of genes on the paternally acquired chromosome 15q11-q13. Phenotypical characteristics of PWS include infantile hypotonia, short stature, incomplete pubertal development, hyperphagia and morbid obesity. Hypothalamic dysfunction in controlling body weight and food intake is a hallmark of PWS. Neuroimaging studies have demonstrated that PWS subjects have a...
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