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Mutation of cancer driver MLL2 results in transcription stress and genome instability

ABSTRACT: Mutation of cancer driver MLL2 results in transcription stress and genome instability

PROVIDER: PRJNA296083 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR2431800.fastq.gz	Fastqsanger.gz
	SRR2431810.fastq.gz	Fastqsanger.gz
	SRR2431820.fastq.gz	Fastqsanger.gz
	SRR2432160.fastq.gz	Fastqsanger.gz
	SRR2432240.fastq.gz	Fastqsanger.gz

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Mutation of cancer driver MLL2 results in transcription stress and genome instability.

Project description:Genome instability is a recurring feature of tumorigenesis. Mutation in MLL2, encoding a histone methyltransferase, is a driver in numerous different cancer types, but the mechanism is unclear. Here, we present evidence that MLL2 mutation results in genome instability. Mouse cells in which MLL2 gene deletion can be induced display elevated levels of sister chromatid exchange, gross chromosomal aberrations, 53BP1 foci, and micronuclei. Human MLL2 knockout cells are characterized by genome instability as well. Interestingly, MLL2 interacts with RNA polymerase II (RNAPII) and RECQL5, and, although MLL2 mutated cells have normal overall H3K4me levels in genes, nucleosomes in the immediate vicinity of RNAPII are hypomethylated. Importantly, MLL2 mutated cells display signs of substantial transcription stress, and the most affected genes overlap with early replicating fragile sites, show elevated levels of γH2AX, and suffer frequent mutation. The requirement for MLL2 in the maintenance of genome stability in genes helps explain its widespread role in cancer and points to transcription stress as a strong driver in tumorigenesis.

| S-EPMC4762426 | biostudies-literature

Mutation of cancer driver MLL2 results in transcription stress and genome instability

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-04-13 | E-GEOD-73130 | biostudies-arrayexpress

Mutation of cancer driver MLL2 results in transcription stress and genome instability

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-04-13 | GSE73130 | GEO

PRMT1-mediated methylation regulates MLL2 stability and gene expression

Project description:The interplay between multiple transcription factors precisely regulates eukaryotic transcription. Here, we report that the protein methyltransferases, MLL2 and PRMT1, interact directly and act collectively to regulate gene expression. PRMT1 binds to the N-terminal region of MLL2, considered an intrinsically disordered region, and methylates multiple arginine residues within its RGG/RG motifs. Notably, overexpression of PRMT1 decreased poly-ubiquitylation of MLL2, whereas mutations on methylation sites in MLL2 increased MLL2 poly-ubiquitylation, suggesting that PRMT1-mediated methylation stabilizes MLL2. MLL2 and PRMT1 cooperatively stimulated the expression of a chromosomal reporter gene in a PRMT1-mediated, MLL2-methylation–dependent manner. RNA-seq analysis found that MLL2 and PRMT1 jointly regulate the expression of genes involved in cell membrane and extracellular matrix functions, and depletion of either resulted in impaired cell migration and invasion. Our study provides evidence that PRMT1-mediated MLL2 methylation regulates MLL2 protein stability and the expression of their target genes.

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Rps15 mutation drives B cell malignancy through translational rewiring, oxidative stress and genomic instability

Project description:Ribosomal protein mutations are increasingly associated with cancer risk and thought to perturb ribosome function. At the same time, they reportedly activate p53, a critical anti-cancer barrier. To determine how these mutations overcome this protective block to enable tumorigenesis, we generated an in vivo model of the hotspot Rps15-S138F mutation identified as a putative driver of chronic lymphocytic leukemia. Under pre-leukemic conditions, this mutation induced protein instability, ribosome biogenesis defects and altered translation resulting in oxidative stress, DNA damage and induction of a p53-dependent response that promote initial cellular hypo-proliferation. However, aged mice with mutated Rps15 eventually developed B-cell leukemia (37% penetrance), which exhibited increased Myc activity with strong pro-survival and proliferation signatures. Mutant Rps15 thus induces both hypo- and hyper-proliferative signals, initially weighted towards cell cycle arrest; and that through translational rewiring, oxidative stress, DNA damage response defects and genomic instability set the stage for the acquisition of additional driving mutations, such as TP53 deletion, that can overcome this cell cycle block to trigger tumorigenesis.

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Project description:We have discovered a striking connection between mitochondrial dysfunction and epigenomic instability, manifested by global biallelic DNA cytosine 5-methylation and loss of 5-hydroxymethycytosine within succinate dehydrogenase (SDH)-null gastrointestinal stromal tumors (GIST) relative to those bearing KIT or PDGFRA tyrosine kinase driver mutations. The duality of Krebs versus kinase molecular and epigenomic profiles in GIST provides compelling evidence linking mitochondrial process to nuclear structure and function and underscores an essential role for succinate metabolism in the maintenance of epigenomic programming and tumor suppression. Bisulfite-converted DNA from 144 samples were analyzed with the Illumina GoldenGate Methylation Cancer Panel I array.

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Deletion of UTX, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome.

Project description:Kabuki syndrome (KS) is a rare multiple congenital anomalies/mental retardation (MCA/MR) syndrome described in 19811,2. In 2010, exome sequencing identified MLL2 mutations in patients with KS3. Since then, 5 studies identified a mutation in MLL2 in 56-75,6% of KS patients3-7. Here, we describe 2 KS and 1 KS-like patient with a de novo partial or complete deletion of UTX, a histone demethylase interacting with MLL2 in gene regulation. UTX locates on the X chromosome and we showed that the X chromosome with the deleted copy of UTX is preferentially inactivated despite the fact that UTX escapes X-inactivation. This study unveiled deletion of UTX as a second cause of KS and highlights the growing role of histone methylase/demethylase in MCA/MR syndrome.

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RNAseq of mll2wt and mll2[Y2602A] mESC and EpiLC

Project description:PolyA RNAseq of mouse ESCs and EpiLCs carrying a homozygous point mutation in the catalytic domain of mll2[Y2602A]. Total RNA was isolated from cell pellets using NEB Monarch Total RNA Miniprep Kit and libraries prepared using NEBNext RNA Ultra II kit (NEB E7770S, input: 350 ng of total RNA). Libraries were multiplexed and sequenced on a NextSeq500 (Paired-End; read length 40). Each sample is present in 3 biological replicates.

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