Suv4‑20h1 promotes G1 to S phase transition by downregulating p21WAF1/CIP1 expression in chronic myeloid leukemia K562 cells

Wu, Yupeng; Wang, Yadong; Liu, Ming; Nie, Min; Wang, Ying; Deng, Yexuan; Yao, Bing; Gui, Tao; Li, Xinyu; Ma, Lingling; Guo, Chan; Ma, Chi; Ju, Junyi; Zhao, Quan

doi:10.3892/ol.2018.8092

Cited by 7 publications

(11 citation statements)

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“…7A); this was not due to increased cell death in the mutants (Fig. 7B), supporting the hypothesis that KMT5B expression contributes to regulation of cell division ( 36 , 37 ) and predicted as cancer enrichments in the hDEG analyses. We have reported persistent lower body weight and shorter body length in the Kmt5b gene trap haploinsufficient mouse model on a C57BL/6N strain background ( 33 ).…”

Section: Resultssupporting

confidence: 80%

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

et al. 2023

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Pathogenic variants in KMT5B , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM # 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.

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Section: Resultssupporting

confidence: 80%

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

et al. 2023

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“…A portion of KMT5B human patients have also been reported with growth problems (Wickramasekara & Stessman, 2019). Given the links between H4K20 methylation and cell proliferation (Vougiouklakis et al, 2015; Wu et al, 2018), it is tempting to hypothesize that this effect is due to changes in cell proliferation. Lean muscle mass and body fat are known to contribute substantially to body weight in mice (Reed et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Kmt5a and Kmt5b null mouse models have been associated with embryonic or perinatal lethality, while Kmt5c null mice have no apparent phenotype (Oda et al, 2009; Schotta et al, 2008), highlighting an importance for KMT5B and H4K20me2 in organismal development. Indeed, H4K20me2 has been implicated in critical cell processes such as, cell cycle, DNA replication, stem cell maintenance, and repair of DNA double‐stranded breaks (Boonsanay et al, 2016; Machado & Relaix, 2016; Schotta et al, 2008; Vougiouklakis et al, 2015; Wu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Differential effects by sex with Kmt5b loss

et al. 2021

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Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in genetic studies of neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet, its role in the brain is not known. The goal of this work was to neurodevelopmentally characterize the effect(s) of KMT5B haploinsufficiency using a mouse model. A Kmt5b gene‐trap mouse line was obtained from the Knockout Mouse Project. Wild type (WT) and heterozygous (HET) mice were subjected to a comprehensive neurodevelopmental test battery to assess reflexes, motor behavior, learning/memory, social behavior, repetitive movement, and common ASD comorbidities (obsessive compulsion, depression, and anxiety). Given the strong sex bias observed in the ASD patient population, we tested both a male and female cohort of animals and compared differences between genotypes and sexes. HET mice were significantly smaller than WT littermates starting at postnatal day 10 through young adulthood which was correlated with smaller brain size (i.e., microcephaly). This was more severe in males than females. HET male neonates also had delayed eye opening and significantly weaker reflexes than WT littermates. In young adults, significant differences between genotypes relative to anxiety, depression, fear, and extinction learning were observed. Interestingly, several sexually dimorphic differences were noted including increased repetitive grooming behavior in HET females and an increased latency to hot plate response in HET females versus a decreased latency in HET males. Lay Summary Lysine methyl transferase 5B (KMT5B) has been recently highlighted as a risk gene in neurodevelopmental disorders (NDDs), specifically, autism spectrum disorder (ASD) and intellectual disability (ID); yet its role in the brain is not known. Our study indicates that mice lacking one genomic copy of Kmt5b show deficits in neonatal reflexes, sociability, repetitive stress‐induced grooming, changes in thermal pain sensing, decreased depression and anxiety, increased fear, slower extinction learning, and lower body weight, length, and brain size. Furthermore, several outcomes differed by sex, perhaps mirroring the sex bias in ASD.

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“…Lysine-specific demethylase (LSD1/KDM1A) is a key regulator of histone H3K4 and H3K9 mono- and dimethylation [96]. It is commonly overexpressed and correlated with a poor prognosis in different human cancers [97,98,99]. LSD1 regulates p21 cip1/waf1 [100] via demethylation of histone and non-histone targets, including p53 and DNMT1 [101], and controls the cell cycle via demethylation of Rb, interaction with long noncoding RNAs (lncRNAs) (including HOTAIR), and demethylation of AGO2, a key element of the RNA-induced silencing complex [96,102].…”

Section: Epigenetic Regulation Of P21cip1/waf1mentioning

confidence: 99%

Epigenetic Regulation of p21cip1/waf1 in Human Cancer

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et al. 2019

Cancers

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p21cip1/waf1 is a central regulator of cell cycle control and survival. While mutations are rare, it is commonly dysregulated in several human cancers due to epigenetic mechanisms influencing its transcriptional control. These mechanisms include promoter hypermethylation as well as additional pathways such as histone acetylation or methylation. The epigenetic regulators include writers, such as DNA methyltransferases (DNMTs); histone acetyltransferases (HATs) and histone lysine methyltransferases; erasers, such as histone deacetylases (HDACs); histone lysine demethylases [e.g., the Lysine Demethylase (KDM) family]; DNA hydroxylases; readers, such as the methyl-CpG-binding proteins (MBPs); and bromodomain-containing proteins, including the bromo- and extraterminal domain (BET) family. We further discuss the roles that long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play in the epigenetic control of p21cip1/waf1 expression and its function in human cancers.

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Suv4‑20h1 promotes G1 to S phase transition by downregulating p21WAF1/CIP1 expression in chronic myeloid leukemia K562 cells

Cited by 7 publications

References 24 publications

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Differential effects by sex with Kmt5b loss

Epigenetic Regulation of p21cip1/waf1 in Human Cancer

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