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Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., Krasemann, S., Lichtenthaler, S.F., Muller, S.A., Colombo, A., Monasor, L.S., Tahirovic, S., Herms, J., Willem, M., Pettkus, N., Butovsky, O., Bartenstein, P., Edbauer, D., Rominger, A., Erturk, A., Grathwohl, S.A., Neher, J.J., Holtzman, D.M., Meyer-Luehmann, M., and Haass, C.
Nat Neurosci, 2019, [Epub ahead of print].
doi: 10.1038/s41593-018-0296-9


Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE

Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.

Sonal, Ganzinger, K.A., Vogel, S.K., Mucksch, J., Blumhardt, P., and Schwille, P.
J Cell Sci, 2018, 132, [Epub ahead of print].
(IMPRS-LS students are in bold)
doi: 10.1242/jcs.219899

Myosin-II activity generates a dynamic steady state with continuous actin turnover in a minimal actin cortex.

Dynamic reorganization of the actomyosin cytoskeleton allows fast modulation of the cell surface, which is vital for many cellular functions. Myosin-II motors generate the forces required for this remodeling by imparting contractility to actin networks. However, myosin-II activity might also have a more indirect contribution to cytoskeletal dynamics; it has been proposed that myosin activity increases actin turnover in various cellular contexts, presumably by enhancing disassembly. In vitro reconstitution of actomyosin networks has confirmed the role of myosin in actin network disassembly, but the reassembly of actin in these assays was limited by factors such as diffusional constraints and the use of stabilized actin filaments. Here, we present the reconstitution of a minimal dynamic actin cortex, where actin polymerization is catalyzed on the membrane in the presence of myosin-II activity. We demonstrate that myosin activity leads to disassembly and redistribution in this simplified cortex. Consequently, a new dynamic steady state emerges in which the actin network undergoes constant turnover. Our findings suggest a multifaceted role of myosin-II in the dynamics of the eukaryotic actin cortex. This article has an associated First Person interview with the first author of the paper.

Scacchetti, A., Brueckner, L., Jain, D., Schauer, T., Zhang, X., Schnorrer, F., van Steensel, B., Straub, T., and Becker, P.B.
Life Sci Alliance, 2018, 1, e201800024.
(IMPRS-LS students are in bold)
doi: 10.26508/lsa.201800024

CHRAC/ACF contribute to the repressive ground state of chromatin

Telomeres and the shelterin complex cap and protect the ends of chromosomes. Telomeres are flanked by the subtelomeric sequences that have also been implicated in telomere regulation, although their role is not well defined. Here, we show that, in Schizosaccharomyces pombe, the telomere-associated sequences (TAS) present on most subtelomeres are hyper-recombinogenic, have metastable nucleosomes, and unusual low levels of H3K9 methylation. Ccq1, a subunit of shelterin, protects TAS from nucleosome loss by recruiting the heterochromatic repressor complexes CLRC and SHREC, thereby linking nucleosome stability to gene silencing. Nucleosome instability at TAS is independent of telomeric repeats and can be transmitted to an intrachromosomal locus containing an ectopic TAS fragment, indicating that this is an intrinsic property of the underlying DNA sequence. When telomerase recruitment is compromised in cells lacking Ccq1, DNA sequences present in the TAS promote recombination between chromosomal ends, independent of nucleosome abundance, implying an active function of these sequences in telomere maintenance. We propose that Ccq1 and fragile subtelomeres co-evolved to regulate telomere plasticity by controlling nucleosome occupancy and genome stability.

De Oliveira, T., Ramakrishnan, M., Diamanti, M.A., Ziegler, P.K., Brombacher, F., and Greten, F.R.
Oncogene, 2018, [Epub ahead of print].
doi: 10.1038/s41388-018-0551-2

Loss of Stat6 affects chromatin condensation in intestinal epithelial cells causing diverse outcome in murine models of inflammation-associated and sporadic colon carcinogenesis.

While great advances have been achieved regarding the genetic basis of colorectal cancer, the complex role of cell-cell communication and cytokine-induced signaling during its pathogenesis remains less understood. Signal transducer and activator of transcription 6 (Stat6) is the main transcription factor of interleukin-4 (IL-4) signaling and its participation in the development of various tumor types has been already reported. Here we aimed to examine the contribution of Stat6 in intestinal epithelial cells (IEC) in mouse models of intestinal carcinogenesis. Wild-type (WT), Stat6 knockout (Stat6-/-), and intestinal epithelial cell-specific IL-4Rα knockout (Il-4rαΔIEC) mice were subjected to colitis-associated (AOM/DSS) and colitis-independent (sporadic) carcinogenesis. IEC proliferation, apoptosis and RNA expression were evaluated by immunohistochemical, immunoblot, and RT-PCR analysis. We found that Stat6-/- mice developed more tumors in the colitis-associated carcinogenesis model. This was accompanied by a more pronounced inflammatory response during colitis and an elevated Stat3-dependent proliferation of IEC. Increased sensitivity to DSS-induced colitis was caused by elevated cell death in response to the initial carcinogen exposure as Stat6 deficiency led to increased chromatin compaction affecting DNA damage response in IEC upon treatment with alkylating agents independently of IL-4Rα engagement. Thus, loss of Stat6 caused more severe colitis and increased tumor load, however loss-of-initiated Stat6-/- IEC prevented tumor formation in the absence of overt inflammation. Our data unravel unexpected IL-4-independent functions of Stat6 in chromatin compaction in intestinal epithelial cells ultimately providing both tumor suppressive as well as tumor promoting effects in different models of intestinal tumorigenesis.