Adaptor Proteins, Signal Transducing

Publication Title: 
PloS One

BACKGROUND: Recent studies have demonstrated that activation of autophagy increases the lifespan of organisms from yeast to flies. In contrast to the lifespan extension effect in lower organisms, it has been reported that overexpression of unc-51-like kinase 3 (ULK3), the mammalian homolog of autophagy-specific gene 1 (ATG1), induces premature senescence in human fibroblasts. Therefore, we assessed whether the activation of autophagy would genuinely induce premature senescence in human cells.

Kang, Hyun Tae
Lee, Ki Baek
Kim, Sung Young
Choi, Hae Ri
Park, Sang Chul
Publication Title: 
Trends in Biochemical Sciences

Reversible acetylation has emerged as a key post-translational modification of proteins. Although the number of acetylated proteins is rapidly growing, the ways in which protein acetyltransferases and deacetylases connect with extracellular stimuli remain unclear. Recently, a regulatory network has emerged that controls the expression and activity of SIRT1, a mammalian class-III protein deacetylase. SIRT1 is an important regulator of metabolism, senescence, cancer and, possibly, longevity and is connected with crucial stress-responsive signal-transduction pathways.

Kwon, Hye-Sook
Ott, Melanie
Publication Title: 
The Journal of Clinical Investigation

The enzyme sirtuin 1 (SIRT1) is a critical regulator of many cellular functions, including energy metabolism. However, the precise mechanisms that modulate SIRT1 activity remain unknown. As SIRT1 activity in vitro was recently found to be negatively regulated by interaction with the deleted in breast cancer-1 (DBC1) protein, we set out to investigate whether DBC1 regulates SIRT1 activity in vivo. We found that DBC1 and SIRT1 colocalized and interacted, and that DBC1 modulated SIRT1 activity, in multiple cell lines and tissues.

Escande, Carlos
Chini, Claudia C. S.
Nin, Veronica
Dykhouse, Katherine Minter
Novak, Colleen M.
Levine, James
Van Deursen, Jan
Gores, Gregory J.
Chen, Junjie
Lou, Zhenkun
Chini, Eduardo Nunes
Publication Title: 
PloS One

BACKGROUND: In a variety of organisms, including mammals, caloric restriction improves metabolic status and lowers the incidence of chronic-degenerative diseases, ultimately leading to increased lifespan. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that knockout mice for Eps8, a regulator of actin dynamics, display reduced body weight, partial resistance to age- or diet-induced obesity, and overall improved metabolic status. Alteration in the liver gene expression profile, in behavior and metabolism point to a calorie restriction-like phenotype in Eps8 knockout mice.

Tocchetti, Arianna
Soppo, Charlotte Blanche Ekalle
Zani, Fabio
Bianchi, Fabrizio
Gagliani, Maria Cristina
Pozzi, Benedetta
Rozman, Jan
Elvert, Ralf
Ehrhardt, Nicole
Rathkolb, Birgit
Moerth, Corinna
Horsch, Marion
Fuchs, Helmut
Gailus-Durner, ValÈrie
Beckers, Johannes
Klingenspor, Martin
Wolf, Eckhard
HrabÈ de Angelis, Martin
Scanziani, Eugenio
Tacchetti, Carlo
Scita, Giorgio
Di Fiore, Pier Paolo
Offenh‰user, Nina
Publication Title: 
Stem Cells Translational Medicine

Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epigenome, particularly through demonstrations of direct lineage reprogramming of adult mouse and human fibroblasts to induced pluripotent stem cells (iPSCs) and induced neurons (iNs) under defined conditions. However, human cells appear to be less plastic and have a higher epigenetic hurdle for reprogramming to both iPSCs and iNs. Here, we show that SH2B adaptor protein 1?

Hsu, Yi-Chao
Chen, Su-Liang
Wang, Ya-Jean
Chen, Yun-Hsiang
Wang, Dan-Yen
Chen, Linyi
Chen, Chia-Hsiang
Chen, Hwei-Hsien
Chiu, Ing-Ming
Publication Title: 
Nature Neuroscience

We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects.

De Jager, Philip L.
Srivastava, Gyan
Lunnon, Katie
Burgess, Jeremy
Schalkwyk, Leonard C.
Yu, Lei
Eaton, Matthew L.
Keenan, Brendan T.
Ernst, Jason
McCabe, Cristin
Tang, Anna
Raj, Towfique
Replogle, Joseph
Brodeur, Wendy
Gabriel, Stacey
Chai, High S.
Younkin, Curtis
Younkin, Steven G.
Zou, Fanggeng
Szyf, Moshe
Epstein, Charles B.
Schneider, Julie A.
Bernstein, Bradley E.
Meissner, Alex
Ertekin-Taner, Nilufer
Chibnik, Lori B.
Kellis, Manolis
Mill, Jonathan
Bennett, David A.
Publication Title: 
Nature Neuroscience

Two independent epigenome-wide association studies of Alzheimerís disease cohorts have identified overlapping methylation signals in four loci, ANK1, RPL13, RHBDF2 and CDH23, not previously associated with Alzheimerís disease. These studies also suggest that epigenetic changes contribute more to Alzheimerís disease than expected.

Lord, Jenny
Cruchaga, Carlos
Publication Title: 
JAMA psychiatry

IMPORTANCE: Dysfunction related to ?-aminobutyric acid (GABA)-ergic neurotransmission in the pathophysiology of major psychosis has been well established by the work of multiple groups across several decades, including the widely replicated downregulation of GAD1. Prior gene expression and network analyses within the human hippocampus implicate a broader network of genes, termed the GAD1 regulatory network, in regulation of GAD1 expression.

Ruzicka, W. Brad
Subburaju, Sivan
Benes, Francine M.
Publication Title: 
Translational Psychiatry

Schizophrenia (SZ) is associated with GABA neuron dysfunction in the hippocampus, particularly the stratum oriens of sector CA3/2. A gene expression profile analysis of human postmortem hippocampal tissue followed by a network association analysis had shown a number of genes differentially regulated in SZ, including the epigenetic factors HDAC1 and DAXX. To characterize the contribution of these factors to the developmental perturbation hypothesized to underlie SZ, lentiviral vectors carrying short hairpin RNA interference (shRNAi) for HDAC1 and DAXX were used.

Subburaju, S.
Coleman, A. J.
Ruzicka, W. B.
Benes, F. M.
Publication Title: 
Nature Communications

DNA methylation (DNAm) levels lend themselves for defining an epigenetic biomarker of aging known as the 'epigenetic clock'. Our genome-wide association study (GWAS) of cerebellar epigenetic age acceleration identifies five significant (P<5.0 ◊ 10(-8)) SNPs in two loci: 2p22.1 (inside gene DHX57) and 16p13.3 near gene MLST8 (a subunit of mTOR complex 1 and 2). We find that the SNP in 16p13.3 has a cis-acting effect on the expression levels of MLST8 (P=6.9 ◊ 10(-18)) in most brain regions. In cerebellar samples, the SNP in 2p22.1 has a cis-effect on DHX57 (P=4.4 ◊ 10(-5)).

Lu, Ake T.
Hannon, Eilis
Levine, Morgan E.
Hao, Ke
Crimmins, Eileen M.
Lunnon, Katie
Kozlenkov, Alexey
Mill, Jonathan
Dracheva, Stella
Horvath, Steve


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