A Dual Role for the Histone Methyltransferase PR-SET7/SETD8 and Histone H4 Lysine 20 Monomethylation in the Local Regulation of RNA Polymerase II Pausing

Kapoor-Vazirani, Priya; Vertino, Paula M.

doi:10.1074/jbc.m113.520783

Cited by 42 publications

(44 citation statements)

References 77 publications

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“…When genes normally enriched for H4K20me1 are analyzed after PRSET7 knockdown, a large subset of the genes' expression increased while others decreased (Beck et al 2012;Wang et al 2008). This suggests that H4K20me1 plays a dual role in both transcriptional repression as well as activation, and its effect on gene expression is heavily influenced by the acetylation of neighboring lysine sixteen (H4K16) (Beck et al 2012;Kapoor-Vazirani and Vertino 2014). A recent study found that H4K20me1 can promote the recruitment of the MSL complex, leading to acetylation of H4K16 around the TSS of genes and promoting their transcription (Kapoor-Vazirani and Vertino 2014).…”

Section: : H4k20methylationmentioning

confidence: 97%

“…H4K20me1 is thought to be established early across the Xi, and while its role in XCI is not fully understood, there is evidence that it may be critical in repressing gene expression in Domain 1, up-regulating the expression of escape genes and providing a substrate for H4K20me3 in Domain 2 (Beck et al 2012;Chadwick 2007;Kapoor-Vazirani and Vertino 2014;Wang et al 2008). H4K20me3 on the other hand is thought to play a more straight forward role, arising in the presence of HP1α in Domain 2 and promoting gene silencing by inhibiting transcription (Kapoor-Vazirani et al 2011;Kapoor-Vazirani and Vertino 2014;Wongtawan et al 2011).…”

Section: : H4k20methylationmentioning

confidence: 99%

“…H4K20me3 on the other hand is thought to play a more straight forward role, arising in the presence of HP1α in Domain 2 and promoting gene silencing by inhibiting transcription (Kapoor-Vazirani et al 2011;Kapoor-Vazirani and Vertino 2014;Wongtawan et al 2011).…”

Section: : H4k20methylationmentioning

confidence: 99%

“…This leads to H3K9me3 and H4K20me3 enrichment as well as H3K9me2 and H4K20me1 depletion in Domain 2 heterochromatin. HP1 binds H3K9me3, which is needed for the recruitment of SUV420H2 as well as the enzyme DNMT3b, which methylates the CpG island promoters along the Xi ( Figure 4) (Chan et al 2011;Kapoor-Vazirani and Vertino 2014;Minkovsky et al 2014).…”

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confidence: 99%

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The making of a Barr body: the mosaic of factors that eXIST on the mammalian inactive X chromosome

Dixon-McDougall

Brown

2016

Biochem. Cell Biol.

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During X-chromosome inactivation (XCI), nearly an entire X chromosome is permanently silenced and converted into a Barr body, providing dosage compensation for eutherians between the sexes. XCI is facilitated by the upregulation of the long non-coding RNA gene, XIST, which coats its chromosome of origin, recruits heterochromatin factors, and silences gene expression. During XCI, at least two distinct types of heterochromatin are established, and in this review we discuss the enrichment of facultative heterochromatin marks such as H3K27me3, H2AK119ub, and macroH2A as well as pericentric heterochromatin marks such as HP1, H3K9me3, and H4K20me3. The extremely stable maintenance of silencing is a product of reinforcing interactions within and between these domains. This paper "Xplores" the current knowledge of the pathways involved in XCI, how the pathways interact, and the gaps in our understanding that need to be filled.

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Section: : H4k20methylationmentioning

confidence: 97%

Section: : H4k20methylationmentioning

confidence: 99%

Section: : H4k20methylationmentioning

confidence: 99%

mentioning

confidence: 99%

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The making of a Barr body: the mosaic of factors that eXIST on the mammalian inactive X chromosome

Dixon-McDougall

Brown

2016

Biochem. Cell Biol.

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“…It is difficult to establish whether H4K20me1 is a stable mark or an intermediate substrate that precedes H4K20me2 and H4K20me3. Nevertheless, H4K20me1 is associated both with active transcription, by regulating H4K16 acetylation and release of Pol II promoter-proximal pausing 152 , and with silencing of genomic regions, including the inactive X chromosome [153][154][155] . The role of H4K20me2 in regulation of transcription is not well understood, but its co-localization with H4K20me3, which is mainly linked to gene silencing 156,157 and heterochromatin formation, suggests that it has a role in transcription repression.…”

Section: Regulation Of Silencing and Replication By H4k20mentioning

confidence: 99%

Sound of silence: the properties and functions of repressive Lys methyltransferases

Mozzetta¹,

Boyarchuk²,

Pontis³

et al. 2015

Nat Rev Mol Cell Biol

165

162

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The methylation of histone Lys residues by Lys methyltransferases (KMTs) regulates chromatin organization and either activates or represses gene expression, depending on the residue that is targeted. KMTs are emerging as key components in several cellular processes, and their deregulation is often associated with pathogenesis. Here, we review the current knowledge on the main KMTs that are associated with gene silencing: namely, those responsible for methylating histone H3 Lys 9 (H3K9), H3K27 and H4K20. We discuss their biochemical properties and the various mechanisms by which they are targeted to the chromatin and regulate gene expression, as well as new data on the interplay between them and other chromatin modifiers.

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Select human cancer mutants of NRMT1 alter its catalytic activity and decrease N‐terminal trimethylation

et al. 2017

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A subset of B-cell lymphoma patients have dominant mutations in the histone H3 lysine 27 (H3K27) methyltransferase EZH2, which change it from a monomethylase to a trimethylase. These mutations occur in aromatic resides surrounding the active site and increase growth and alter transcription. We study the N-terminal trimethylase NRMT1 and the N-terminal monomethylase NRMT2. They are 50% identical, but differ in key aromatic residues in their active site. Given how these residues affect EZH2 activity, we tested whether they are responsible for the distinct catalytic activities of NRMT1/2. Additionally, NRMT1 acts as a tumor suppressor in breast cancer cells. Its loss promotes oncogenic phenotypes but sensitizes cells to DNA damage. Mutations of NRMT1 naturally occur in human cancers, and we tested a select group for altered activity. While directed mutation of the aromatic residues had minimal catalytic effect, NRMT1 mutants N209I (endometrial cancer) and P211S (lung cancer) displayed decreased trimethylase and increased monomethylase/dimethylase activity. Both mutations are located in the peptide-binding channel and indicate a second structural region impacting enzyme specificity. The NRMT1 mutants demonstrated a slower rate of trimethylation and a requirement for higher substrate concentration. Expression of the mutants in wild type NRMT backgrounds showed no change in N-terminal methylation levels or growth rates, demonstrating they are not acting as dominant negatives. Expression of the mutants in cells lacking endogenous NRMT1 resulted in minimal accumulation of N-terminal trimethylation, indicating homozygosity could help drive oncogenesis or serve as a marker for sensitivity to DNA damaging chemotherapeutics or γ-irradiation.

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A Dual Role for the Histone Methyltransferase PR-SET7/SETD8 and Histone H4 Lysine 20 Monomethylation in the Local Regulation of RNA Polymerase II Pausing

Cited by 42 publications

References 77 publications

The making of a Barr body: the mosaic of factors that eXIST on the mammalian inactive X chromosome

The making of a Barr body: the mosaic of factors that eXIST on the mammalian inactive X chromosome

Sound of silence: the properties and functions of repressive Lys methyltransferases

Select human cancer mutants of NRMT1 alter its catalytic activity and decrease N‐terminal trimethylation

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