The epigenetic factor Kmt2a/Mll1 regulates neural progenitor proliferation and neuronal and glial differentiation

Huang, Yin; Shih, Hung-Yu; Lin, Sheng Jia; Chiu, Ching-Chi; Lin, Tay-Jyi; Yeh, Tu Hsueh; Yi, Cheng

doi:10.1002/dneu.22235

Cited by 35 publications

(27 citation statements)

References 24 publications

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“…The majority of the identified variants were predicted to cause premature termination of the protein product, leading to severe reduction of protein or to a mature protein product, lacking the SET domain and thus, losing the histone-methyltransferase activity. Major role of KMT2A in neural progenitor proliferation, neuronal and glial differentiation and synaptic plasticity has been shown by data obtained in knock-out mice and zebrafish embryos [33,34]. Until today, only five missense variants located in the N-terminal region between the two AT hooks, in the CXXC zinc finger domains and the PHD domains [17,20,23,24].…”

Section: Discussionmentioning

confidence: 99%

Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome

et al. 2017

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Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2A variants are non-sense and frameshift variants causing a typical form of Wiedemann-Steiner syndrome. We studied KMT2A gene in a cohort of 200 patients with unexplained syndromic and non-syndromic ID and identified four novel variants, one splice and three missense variants, possibly deleterious. We used primary cells from the patients and molecular approaches to determine the deleterious effects of those variants on KMT2A expression and function. For the putative splice variant c.11322-1G>A, we showed that it led to only one nucleotide deletion and loss of the C-terminal part of the protein. For two studied KMT2A missense variants, c.3460C>T (p.(Arg1154Trp)) and c.8558T>G (p.(Met2853Arg)), located at the cysteine-rich CXXC domain and the transactivation domain of the protein, respectively, we found altered KMT2A target genes expression in patient's fibroblasts compared to controls. Furthermore, we found a disturbed subcellular distribution of KMT2A for the c.3460C>T mutant. Taken together, our results demonstrated the deleterious impact of the splice variant and of the missense variants located at two different functional domains and suggested reduction of KMT2A function as the disease-causing mechanism.

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Section: Discussionmentioning

confidence: 99%

Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome

et al. 2017

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“…KMT2A also plays an important role in maintaining specific gene expression for neurogenesis, hematopoiesis, and osteogenesis [ 7 – 9 ]. Conditional KMT2A knockout regulates the survival, proliferation, and differentiation of subventricular zone neural stem cells in postnatal mouse brains [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Conditional KMT2A knockout regulates the survival, proliferation, and differentiation of subventricular zone neural stem cells in postnatal mouse brains [ 7 ]. In zebrafish embryos, disrupting Kmt2a expression by using morpholino antisense oligonucleotides and a dominant-negative variant resulted in the downregulated proliferation of neural progenitors, premature differentiation of neurons, and impaired gliogenesis [ 9 ]. However, the role of KMT2A and its downstream signaling in brain tumors, particularly the role of epigenetic regulatory activity, remains to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation

et al. 2017

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Glioblastomas are among the most fatal brain tumors; however, the molecular determinants of their tumorigenic behavior are not adequately defined. In this study, we analyzed the role of KMT2A in the glioblastoma cell line U-87 MG. KMT2A knockdown promoted cell proliferation. Moreover, it increased the DNA methylation of NOTCH1 and NOTCH3 and reduced the expression of NOTCH1 and NOTCH3. NOTCH1 or NOTCH3 activation inhibited U-87 MG cell proliferation, whereas NOTCH1 and NOTCH3 inhibition by shRNAs induced cell proliferation, thus demonstrating the tumor-suppressive ability of NOTCH1 and NOTCH3 in U-87 MG cells. The induced cell proliferation caused by KMT2A knockdown could be nullified by using either constitutively active NOTCH1 or constitutively active NOTCH3. This result demonstrates that KMT2A positively regulates NOTCH1 and NOTCH3 and that this mechanism is essential for inhibiting the U-87 MG cell proliferation. The role of KMT2A knockdown in promoting tumor growth was further confirmed in vivo by transplanting U-87 MG cells into the brains of zebrafish larvae. In conclusion, we identified KMT2A-NOTCH as a negative regulatory cascade for glioblastoma cell proliferation, and this result provides important information for KMT2A- or NOTCH-targeted therapeutic strategies for brain tumors.

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“…Histone methylation can be regulated Kdm 5a, Kdm 5b [64] and Kmt 2a [65]. Kdm 5a and Kdm 5b can inhibit H3K4me3 [66], however, Kmt 2a, a methyltransferase, can activate H3K4me3 [67]. We found that cyadox and rGH increased the level of Kdm 5a and Kdm 5b expression.…”

Section: Discussionmentioning

confidence: 62%

The role of cyadox and recombinant growth hormone (rGH) on the promotion of growth through epigenetics

Liu

Zhu

et al. 2020

Preprint

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Background: Cyadox is an effective growth-promoting antibiotic, which is similar to the role of recombinant growth hormone (rGH). Current studies have shown that cyadox can promote animal growth through altering intestinal microflora, improving protein utilization and increasing protein synthesis. Increasing evidence suggests that epigenetics are also closely related to growth. However, the potential role of epigenetics in the cyadox for growth has not been explored. Results: Here, we used recombinant growth hormone (rGH) and cyadox to study the relationship between growth and changes in epigenetics including DNA methylation, histone modification and chromatin structure. Bisulfite DNA sequencing (BSP) assay suggested that cyadox and rGH treatments increased IGF-1 expression partially by hypomethylation at CpG sites within the promoter region of IGF-1, which was regulated by DNA methyltransferases (DNMTs). We also observed an enrichment of H3K4me3 and H3K27ac at the promoter regions of IGF-1 by ChIP-qPCR assay, which contributed to an increase in IGF-1 transcription. In addition, immunofluorometric assay displayed cellular accessible chromatin structure following the treatment of cyadox and rGH, facilitating the combination of transcription factors and DNA and thus enhancing gene transcription. Conclusions: Taken together, our findings indicated that cyadox and rGH promote cell growth partially through epigenetic changes, providing a prospect for the development of animal growth-promoting drugs in the future.

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The epigenetic factor Kmt2a/Mll1 regulates neural progenitor proliferation and neuronal and glial differentiation

Cited by 35 publications

References 24 publications

Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome

Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome

Epigenetic regulation of NOTCH1 and NOTCH3 by KMT2A inhibits glioma proliferation

The role of cyadox and recombinant growth hormone (rGH) on the promotion of growth through epigenetics

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