Neural crest specification and migration independently require NSD3-related lysine methyltransferase activity

Jacques-Fricke, Bridget T.; Gammill, Laura S.

doi:10.1091/mbc.e13-12-0744

Cited by 22 publications

(28 citation statements)

References 75 publications

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“…In the embryonal neural crest border region histone methyltransferase NSD3 activates MSX1 transcription probably via H3K4-methylation [52, 53]. In myoblasts and neural crest cells HDAC1 and HDAC3, respectively, inhibits MSX1 expression demonstrating an activating input of histone acetylation in these cell types [54, 55].…”

Section: Discussionmentioning

confidence: 99%

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

et al. 2016

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Recently, we identified deregulated expression of the B-cell specific transcription factor MEF2C in T-cell acute lymphoid leukemia (T-ALL). Here, we performed sequence analysis of a regulatory upstream section of MEF2C in T-ALL cell lines which, however, proved devoid of mutations. Unexpectedly, we found strong conservation between the regulatory upstream region of MEF2C (located at chromosomal band 5q14) and an intergenic stretch at 7q11 located between STAG3L4 and AUTS2, covering nearly 20 kb. While the non-coding gene STAG3L4 was inconspicuously expressed, AUTS2 was aberrantly upregulated in 6% of T-ALL patients (public dataset GSE42038) and in 3/24 T-ALL cell lines, two of which represented very immature differentiation stages. AUTS2 expression was higher in normal B-cells than in T-cells, indicating lineage-specific activity in lymphopoiesis. While excluding chromosomal aberrations, examinations of AUTS2 transcriptional regulation in T-ALL cells revealed activation by IL7-IL7R-STAT5-signalling and MEF2C. AUTS2 protein has been shown to interact with polycomb repressor complex 1 subtype 5 (PRC1.5), transforming this particular complex into an activator. Accordingly, expression profiling and functional analyses demonstrated that AUTS2 activated while PCGF5 repressed transcription of NKL homeobox gene MSX1 in T-ALL cells. Forced expression and pharmacological inhibition of EZH2 in addition to H3K27me3 analysis indicated that PRC2 repressed MSX1 as well. Taken together, we found that AUTS2 and MEF2C, despite lying on different chromosomes, share strikingly similar regulatory upstream regions and aberrant expression in T-ALL subsets. Our data implicate chromatin complexes PRC1/AUTS2 and PRC2 in a gene network in T-ALL regulating early lymphoid differentiation.

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Section: Discussionmentioning

confidence: 99%

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

et al. 2016

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“…In cells NSD3 functions as a transcriptional activator, but NSD3's KMTase activity may contribute only partially to its geneactivating role. For example, NSD3 regulates neural crest specification and migration and is required for activation of neural crest transcription factors Sox10, Snail2, Sox9 and FoxD3, but the only locus at which NSD3 is responsible for H3K36 dimethylation is Sox10 [72]. Similar to NSD1, NUP98-NSD3 fusion proteins have been reported in AML and myelodysplastic syndrome [73,74].…”

Section: H3k36me3mentioning

confidence: 99%

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

2016

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Methylation at histone 3, lysine 36 (H3K36) is a conserved epigenetic mark regulating gene transcription, alternative splicing and DNA repair. Genes encoding H3K36 methyltransferases (KMTases) are commonly overexpressed, mutated or involved in chromosomal translocations in cancer. Molecular biology studies have demonstrated that H3K36 KMTases regulate oncogenic transcriptional programs. Structural studies of the catalytic SET domain of H3K36 KMTases have revealed intriguing opportunities for design of small molecule inhibitors. Nevertheless, potent inhibitors for most H3K36 KMTases have not yet been developed, underlining the challenges associated with this target class. As we now have strong evidence linking H3K36 KMTases to cancer, drug development efforts are predicted to yield novel compounds in the near future. Cellular development and differentiation are controlled by post-translational modifications on DNA and histone proteins, forming an epigenetic (above the genes) regulatory network. Disruption of epigenetic pathways is a nearly universal feature of cancer, causing aberrations in gene expression and genome integrity (reviewed in [1]). A key group of epigenetic enzymes disrupted in cancer is the lysine methyltransferases (KMTases), which install methyl groups on histone proteins. In cancer cells, methylation performed by KMTases drives proliferation and halts differentiation by modifying gene transcription and other DNA-templated processes [2][3][4]. Over the past decade, KMTases have emerged as important drug targets for both industrial and academic research groups. Some progress has been made, most notably by selective inhibitors for the EZH2 and DOT1L KMTases that have reached clinical trials for the treatment of nonHodgkin lymphoma and acute leukemia, respectively [5,6]. Nevertheless, selective and cell permeable inhibitors for many KMTases remain unavailable.Methylation at H3K36 represents a particularly important chromatin mark implicated in diverse forms of cancer. KMTases with specificity toward H3K36 are overexpressed in cancer cells and have been characterized as regulators of cell growth, differentiation, stemness and DNA repair pathways [7][8][9]. However, very few selective and cell-active small molecule inhibitors of H3K36-specfic KMTases have been reported to date. In this article, we provide an overview of cellular pathways involving H3K36 methylation and discuss the diverse functions carried out by the eight different human H3K36-specific KMTases. Then we analyze structural characteristics of the catalytic SET domain of H3K36 KMTases and evaluate prospects for their inhibition by small molecules. Review Rogawski, Grembecka & Cierpicki We conclude with a discussion of the challenges and o pportunities for targeting these proteins. SPECIAL FOCUS y Epigenetic drug discovery H3K36 methylation regulates diverse processes implicated in cancerH3K36 methylation participates in a wide variety of nuclear pathways. Many of these processes, including transcriptional regulation, alternative spli...

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“…WHSC1L1—the paralog of WHSC1 found on chromosome 8—is a major NSD-family histone methyltransferase thought to facilitate such changes at H3K36 of the neural crest cell transcription factor Sox10 (Jacques-Fricke and Gammill, 2014). Electroporating chick embryos before neural crest cell migration with a dominant negative construct lacking the methylating SET domain resulted in faulty migration: cells began to travel away from the neural tube but stopped short of their destination points (Jacques-Fricke and Gammill, 2014). Additionally, this dominant negative construct disrupted specification, preventing the expression of neural crest-characterizing transcripts Msx1, FoxD3, Sox9 , Sox10, and Snail2, as visualized by in situ hybridization.…”

Section: Whsc1mentioning

confidence: 99%

“…It is unclear exactly how NSD-family proteins regulate neural crest identity and migration patterns. Despite the evidence that WHSC1L1 is a major methylating agent during migration, it only directly methylates at the Sox10 genomic region (Jacques-Fricke and Gammill, 2014); this leaves open possible roles for other NSD family proteins such as WHSC1 in driving as-of-yet unexplored epigenetic modifications during neural crest cell specification and migration. Thus, chromosome 4p deletions characteristic of WHS may indeed impact neural crest development, especially considering the similar structures and functions conserved from WHSC1L1 and WHSC1 , the 4p gene from which it arose by way of a duplication event (Stec et al, 2001).…”

Section: Whsc1mentioning

confidence: 99%

Exploring the developmental mechanisms underlying Wolf-Hirschhorn Syndrome: Evidence for defects in neural crest cell migration

Rutherford

Lowery

2016

Developmental Biology

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Wolf-Hirschhorn Syndrome (WHS) is a neurodevelopmental disorder characterized by mental retardation, craniofacial malformation, and defects in skeletal and heart development. The syndrome is associated with irregularities on the short arm of chromosome 4, including deletions of varying sizes and microduplications. Many of these genotypic aberrations in humans have been correlated with the classic WHS phenotype, and animal models have provided a context for mapping these genetic irregularities to specific phenotypes; however, there remains a significant knowledge gap concerning the cell biological mechanisms underlying these phenotypes. This review summarizes literature that has made recent contributions to this topic, drawing from the vast body of knowledge detailing the genetic particularities of the disorder and the more limited pool of information on its cell biology. Finally, we propose a novel characterization for WHS as a pathophysiology owing in part to defects in neural crest cell motility and migration during development.

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Neural crest specification and migration independently require NSD3-related lysine methyltransferase activity

Cited by 22 publications

References 75 publications

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

Deregulation of polycomb repressor complex 1 modifier AUTS2 in T-cell leukemia

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

Exploring the developmental mechanisms underlying Wolf-Hirschhorn Syndrome: Evidence for defects in neural crest cell migration

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