Unknown,Transcriptomics,Genomics,Proteomics

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Aging-dependent demethylation of regulatory elements correlates with chromatin state and improved insulin secretion by pancreatic ? cells

ABSTRACT: Aging at the cellular level is driven by changes in gene activity and epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic ? cell, key player in glucose homeostasis and diabetes, in adolescent and very old mice. Globally, we observe a general methylation drift resulting in an overall more leveled methylome, suggesting that the maintenance of highly differential methylation patterns becomes compromised with advanced age. Importantly, we discover targeted changes in the methylation status of ? cell proliferation and function genes that go against the global methylation drift, are specific to ? cells, and correlate with repression of the proliferation program and activation of metabolic regulators. These targeted alterations frequently occur at distal cis-regulator elements, and are associated with specific chromatin marks and transcription factor occupancy in young ? cells. Strikingly, we find the insulin secretory response to glucose much improved in mature ? cells in mice, as predicted by the changes in methylome and transcriptome and in contrast to the decline in function observed in aged human ? cells. Thus, aging of terminally differentiated cells in mammals is not always coupled to functional decline. RNA-seq was done on 3 biological replicas from old and three from young beta cells. each sample originated from a pool of 5-10 mic.e H3K27me3 ChIP-seq was done with two replicas for old mice (pool of 4-7 mice) and the rest of the ChIPseq (H3K4me1, H3K27ac and young H3K27me3) was sone with one sample (pool of few mice). BIS-seq was done on one sample from a pool of 10 young mice and one sample of a pool of old mice (18-22 months old)

ORGANISM(S): Mus musculus

SUBMITTER: Dana Avrahami

PROVIDER: E-GEOD-68618 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function.

Avrahami Dana D Li Changhong C Zhang Jia J Schug Jonathan J Avrahami Ran R Rao Shilpa S Stadler Michael B MB Burger Lukas L Schübeler Dirk D Glaser Benjamin B Kaestner Klaus H KH

Cell metabolism 20150827 4

Aging is driven by changes of the epigenetic state that are only partially understood. We performed a comprehensive epigenomic analysis of the pancreatic β cell, key player in glucose homeostasis, in adolescent and very old mice. We observe a global methylation drift resulting in an overall more leveled methylome in old β cells. Importantly, we discover targeted changes in the methylation status of β cell proliferation and function genes that go against the global methylation drift, are specific ...[more]

PMID: 26321660

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Project description:In Arabidopsis, CHG DNA methylation is controlled by the H3K9 methylation mark through a self-reinforcing loop between DNA methyltransferase CHROMOMETHYLASE3 (CMT3) and H3K9 histone methyltransferase KRYPTONITE/SUVH4 (KYP). We report on the structure of KYP in complex with methylated DNA, substrate H3 peptide and cofactor SAH, thereby defining the spatial positioning of the SRA domain relative to the SET domain. The methylated DNA is bound by the SRA domain with the 5mC flipped out of the DNA, while the H3(1-15) peptide substrate binds between the SET and post-SET domains, with the epsilon-ammonium of K9 positioned adjacent to bound SAH. These structural insights complemented by in vivo functional data on key mutants of residues lining the 5mC and H3K9-binding pockets within KYP, establish how methylated DNA recruits KYP to the histone substrate. Together, the structures of KYP and previously reported CMT3 complexes provide insights into molecular mechanisms linking DNA and histone methylation. Plants homozygous for null mutations in the KRYPTONITE H3K9 methyltransferase were stably transformed with transgenes encoding the wildtype KYP protein or transgenes carrying induced point mutations in the KYP active site. The resulting lines were assayed for DNA methylation by whole-genome bisulfite sequencing to learn the efficiency with which wildtype and mutant versions of the KYP protein could restore DNA methylation lost in a kyp mutant. Samples 7 and 8 were run as single Illumina lanes and as such were compared to a previous Col sample (GSM881756), this Col sample was realigned to the TAIR10 genome for this study and as such updated processed files are available with this submission. These samples were used to define kyp mutant CHG context DMRs that were complemented upon introduction of the wildtype KYP protein. Samples 1-6 were run as multiplexed samples and were used to assay the degree of complementation for various point mutants. All plants are in the Col ecotype background.

Dataset Information

Aging-dependent demethylation of regulatory elements correlates with chromatin state and improved insulin secretion by pancreatic ? cells

Publications

Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function.

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