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News 2012

CMBN has come to an end
Announced 31 December 2012

The Centre for Molecular Biology and Neuroscience (CMBN) has come to an end and this website will no longer be updated.

For information about the research carried out in the research groups that comprised CMBN, please see the websites of UiO and OUS as well as the websites of the individual groups.

Best wishes for 2013 to our collaborators and all visitors of the website!

Publication in Molecular Cell on reversal of base modifications in messenger RNA (mRNA) and role in human disease
Announced 31 December 2012

Methylation of mammalian DNA and histone residues are known to regulate transcription, and the discovery of demethylases that remove methylation in DNA and histones provide a basis for the understanding of dynamic regulation of mammalian gene expression. Knowledge on these demethylases has led to a tremendous progress in the understanding of methyl marks in gene regulation and role in numerous diseases.

In mRNA, the methylation of adenosine (6meA) is particularly interesting since it is the most abundant internal modification. The first mRNA demethylase, FTO, was identified recently and 6meA was shown to be a substrate for FTO. Genome-wide association studies have identified a firm link between the human FTO gene, obesity and type II diabetes. In a collaborative study, Dahl (Picture) and colleagues, together with collaborators at the University of Chicago and Beijing, show that ALKBH5 is a second demethylase for 6meA in mRNA (see figure below) and that mice lacking this demethylase are infertile.

Together, the discovery of two proteins that can reverse 6meA modifications from mRNA draws attention to the potential regulatory functions of reversible RNA methylation and the role of 6meA in disease. Insights into the mechanism of this process may well open up new horizons and opportunities for basic as well as translational research.

ALKBH5 mediated demethylation of 6-methyladenine (6meA) in messenger RNA (mRNA)

Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang CM, Li CJ, Vågbø CB, Shi Y, Wang WL, Song SH, Lu Z, Bosmans RP, Dai Q, Hao YJ, Yang X, Zhao WM, Tong WM, Wang XJ, Bogdan F, Furu K, Fu Y, Jia G, Zhao X, Liu J, Krokan HE, Klungland A, Yang YG and He C
ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility
Mol Cell (in press)

Publication in PNAS on suppressive effects of anesthesia on glial Ca2+signaling
Announced 6 November 2012

The article shows that doses of anesthesia insufficient to affect neuronal responses to whisker stimulation suppressed astrocyte calcium signals.

Thrane AS, Thrane VR, Zeppenfeld D, Lou N, Xu Q, Nagelhus EA, Nedergaard M
General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex
Proc Natl Acad Sci U S A (in press)

CMBN 10 year summary report
Announced 6 August 2012

CMBN 10 year summary report The CMBN 10 year summary report is now available.
Publication in Stem Cells identifying a histone H2A dioxygenase required for neural development
Announced 19 September 2012

AlkB homolog 1 (ALKBH1) is one of nine members of the family of mammalian AlkB homologs. Most Alkbh1 deficient mice die during embryonic development, and survivors are characterized by defects in tissues originating from the ectodermal lineage. In this study, we show that ALKBH1 is a histone dioxygenase that acts specifically on histone H2A. Further, we demonstrate that deletion of Alkbh1 in embryonic stem cells leads to upregulation of the core genes involved in pluripotency and that ALKBH1 is required during early differentiation. Our results suggest that ALKBH1 is involved in neural development by modifying the methylation status of histone H2A.

Histone H2A dioxygenase

Ougland R, Lando D, Jonson I, Dahl JA, Moen MN, Nordstrand LM, Rognes T, Lee JT, Klungland A, Kouzarides T, Larsen E
ALKBH1 is a Histone H2A Dioxygenase Involved in Neural Differentiation
Stem Cells (in press)

Publication in Human Molecular Genetics on a new link between Huntington's disease and DNA repair
Announced 5 September 2012

Two CMBN groups have identified a DNA repair gene that modify somatic and germline CAG trinucleotide repeat instability in the Huntingtin gene. Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG:CTG repeat expansion in exon 1 of the gene that encodes the polyglutamine-containing protein Huntingtin. It is shown here that somatic CAG expansions are significantly reduced in several organs of R6/1 mice lacking exon 2 of Nei-like 1 (Neil1). This study further confirm a role of oxidative DNA damage and neurodegeneration. We previously identified (with Cynthia McMurray's group at the Mayo Clinic, Rochester, MA, USA) a role of 8-oxoguanine-DNA glycosylase (OGG1) enzyme in initiation of age-dependent CAG trinucleotide expansion associated with Huntington's disease that occurs in somatic cells. (Kovtun et al., Nature 2007).

Møllersen L, Rowe AD, Illuzzi JL, Hildrestrand GA, Gerhold KJ, Tveterås L, Bjølgerud A, Wilson DM, Bjørås M, Klungland A
Neil1 is a genetic modifier of somatic and germline CAG trinucleotide repeat instability in R6/1 mice
Hum Mol Genet (in press)

Cover story in Science Translational Medicine on a paravascular pathway
Announced 17 August 2012

Science Translational Medicine Cover

CMBN scientists have co-authored the cover story of the current issue of Science Translational Medicine. The article describes paravascular pathways that others call the superhighways or hidden sewers of the brain.

Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M
A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β
Sci Transl Med, 4:147ra111

The article has been featured in several news stories:

Vannkanaler renser hjernen, 5 September 2012

Forklarer hjernens avfallsmekanisme
Dagens Medisin, 11 September 2012

Vannkanaler holder hjernen ren
Nyheter om Nevronor, Norges forskningsråd, 11 September 2012

CMBN annual report 2011
Announced 6 August 2012

CMBN annual report 2009 The CMBN annual report 2011 is now available.
Publication in Nucleic Acids Research on visualization of Flap Endonuclease I (FEN1) during proliferation and repair
Announced 26 July 2012

The structure specific flap endonuclease 1 (FEN1) plays an essential role in long-patch base excision 15 repair (BER) and in DNA replication. Here, the monitoring of the localization and kinetics of endogenous FEN1 is achieved by tagging the Fen1 gene in embryonic stem cells for generating "knockin" mice. In line with the role of FEN1 in processing of Okazaki fragments during DNA replication, FEN1-YFP expression is mainly observed in highly proliferating tissue. In vivo multi-photon fluorescence microscopy demonstrates rapid localization of FEN1 to local laser-induced DNA damage sites in nuclei, providing evidence of a highly mobile protein that accumulates fast at DNA lesion sites with high turnover rate. Inhibition of poly (ADP-ribose) polymerase 1 (PARP1) disrupts FEN1 accumulation at sites of DNA damage, indicating that PARP1 is required for FEN1 recruitment to DNA repair intermediates in BER.

FEN1 visualization

Immunofluorescence staining of endogenous FEN1 (green) and brain cell marker anti-NeuN of Fen1y/y mouse brain 7.5 days after birth. DAPI (blue) stained nuclear DNA. To the right, a merge of blue, red and green channel is shown. The scale bar is 200 μm.

Kleppa L, Mari PO, Larsen E, Lien GF, Godon C, Theil AF, Nesse GJ, Wiksen H, Vermeulen W, Giglia-Mari G, Klungland A
Kinetics of endogenous mouse FEN1 in base excision repair
Nucleic Acids Res (in press)

Publication in Blood descriping novel therapeutic mechanism effective in curing APL
Announced 29 June 2012

Acute promyelocytic leukemia (APL) represents one of the most malignant forms of acute myelogenous leukemia. Despite the aggressiveness of this cancer, it can be effectively cured by two different drugs called all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In an article recently published in the journal Blood the authors describe a novel therapeutic mechanism that explains why ATO is particularely effective in curing APL. These findings may provide important clues to how the ATO-based therapy of APL may be further developed and adapted for treatment of other cancers.

Lång E, Grudic A, Pankiv S, Bruserud O, Simonsen A, Bjerkvig R, Bjørås M, Bøe SO
The arsenic-based cure of acute promyelocytic leukemia promotes cytoplasmic sequestration of PML and PML/RARA through inhibition of PML body recycling
Blood (in press)

Publication in PNAS demonstrating a new function for the cell cycle kinase Cdk1
Announced 29 June 2012

Cell proliferation during normal growth and development of eukaryotic organisms is regulated by cyclin dependent kinases (CDKs). CDKs are the master regulators of the cell cycle, which is the mechanism that controls cell duplication. Cancer cells deceitfully hijack CDKs to drive their uncontrolled cell proliferation. It is therefore very important to understand the function and regulation of CDKs. A team of researchers at CMBN has now discovered a new function for Cdk1 in the model organism budding yeast (Cdk1, also known as Cdc28, is the critical cell cycle regulator in yeast).

Chymkowitch P, Eldholm V, Lorenz S, Zimmermann C, Lindvall JM, Bjørås M, Meza-Zepeda LA, Enserink JM (2012)
Cdc28 kinase activity regulates the basal transcription machinery at a subset of genes
Proc Natl Acad Sci U S A, 109 (26), 10450-5

Publication in Journal of Clinical Investigation on inflammation-mediated colon carcinogenesis
Announced 13 June 2012

In a collaborative study with scientists led by Prof. Leona Samson at MIT, Boston, it is shown that three genes collaborate to protect against inflammation-mediated colon carcinogenesis. More than 15% of cancer deaths worldwide are associated with underlying infections or inflammatory conditions and inflamed tissues harbor elevated etheno-base (ε-base) DNA lesions. The alkyl adenine DNA glycosylase (AAG) recognizes such lesions and provide some protecting against inflammation associated colon cancer. Two other DNA repair enzymes repair ε-base lesions, ALKBH2 and ALKBH3, and could also provide protection against inflammation-mediated colon carcinogenesis. Using established chemically induced colitis and colon cancer models in mice, it is shown here that Alkbh2 and Alkbh3 provide cancer protection similar to that of the DNA glycosylase Aag. Moreover, Alkbh2 and Alkbh3 each display apparent epistasis with Aag. Surprisingly, deficiency in all 3 DNA repair enzymes confers a massively synergistic phenotype, such that animals lacking all 3 DNA repair enzymes cannot survive even a single bout of chemically induced colitis.

Calvo JA, Meira LB, Lee CY, Moroski-Erkul CA, Abolhassani N, Taghizadeh K, Eichinger LW, Muthupalani S, Nordstrand LM, Klungland A, Samson LD
DNA repair is indispensable for survival after acute inflammation
J Clin Invest (in press)

Publication in Nature Protocols on pull-down of the 6th base in genomic DNA
Announced 30 January 2012

Adam Robertson, John Arne Dahl and colleagues at CMBN have published a protocol for identification of the novel 6th DNA base in genomic DNA. The base, 5-hydroxymethylCytosine (5-hmC), was discovered over 30 years ago. At that time, the 5-hmC modification was suggested to be a rare and nonmutagenic DNA damage lesion and therefore was given little attention. In early 2009, 5-hmC was identified again; however, at that time the importance of 5-hmC in epigenetics was realized, as two independent groups began the initial characterization of the 5-hmC modification. Although the function of the 5-hmC modification remains unclear, it has become clear that identifying genomic regions that contain 5-hmC will help to elucidate the function of this base. The protocol described here is based on the procedure developed to isolate 5-hmC–containing DNA in two steps (i) glucosylation of 5-hmC and (ii) the subsequent pull-down of β-glu-5-hmC by JBP1-coated magnetic beads.

Robertson AB, Dahl JA, Ougland R, Klungland A (2012)
Pull-down of 5-hydroxymethylcytosine DNA using JBP1-coated magnetic beads
Nat Protoc, 7 (2), 340-50

Publication in Nature Communications on structure-based mutagenesis of an albumin binding site
Announced 9 January 2012

Scientists in CIR and CMBN published a paper in Nature Communication that reveals the intermolecular interactions of the FcRn-albumin complex.

Albumin is the most abundant protein in blood where it has a pivotal role as a transporter of fatty acids and drugs. Like IgG, albumin has long serum half-life, protected from degradation by pH-dependent recycling mediated by interaction with the neonatal Fc receptor, FcRn. Although the FcRn interaction with IgG is well characterized at the atomic level, its interaction with albumin is not. Here we present structure-based modelling of the FcRn–albumin complex, supported by binding analysis of site-specific mutants, providing mechanistic evidence for the presence of pH-sensitive ionic networks at the interaction interface. These networks involve conserved histidines in both FcRn and albumin domain III. Histidines also contribute to intramolecular interactions that stabilize the otherwise flexible loops at both the interacting surfaces. These results may guide the development of novel albumin variants with altered serum half-life as carriers of drugs.

Andersen JT, Dalhus B, Cameron J, Daba MB, Plumridge A, Evans L, Brennan SO, Gunnarsen KS, Bjørås M, Sleep D, Sandlie I (2012)
Structure-based mutagenesis reveals the albumin-binding site of the neonatal Fc receptor
Nat Commun, 3, 610
PubMed 22215085

Centre for Molecular Biology and Neuroscience (CMBN)
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