%0 Journal Article %J Cell Stem Cell %D 2014 %T Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. %A Sun, Deqiang %A Luo, Min %A Jeong, Mira %A Rodriguez, Benjamin %A Xia, Zheng %A Hannah, Rebecca %A Wang, Hui %A Le, Thuc %A Faull, Kym F %A Chen, Rui %A Gu, Hongcang %A Bock, Christoph %A Meissner, Alexander %A Göttgens, Berthold %A Darlington, Gretchen J %A Li, Wei %A Goodell, Margaret A %K Animals %K Cell Differentiation %K Cells, Cultured %K Cellular Senescence %K Chromatin Immunoprecipitation %K Epigenomics %K Hematopoietic Stem Cells %K Male %K Mice %K Transforming Growth Factor beta %X

To investigate the cell-intrinsic aging mechanisms that erode the function of somatic stem cells during aging, we have conducted a comprehensive integrated genomic analysis of young and aged cells. We profiled the transcriptome, DNA methylome, and histone modifications of young and old murine hematopoietic stem cells (HSCs). Transcriptome analysis indicated reduced TGF-β signaling and perturbation of genes involved in HSC proliferation and differentiation. Aged HSCs exhibited broader H3K4me3 peaks across HSC identity and self-renewal genes and showed increased DNA methylation at transcription factor binding sites associated with differentiation-promoting genes combined with a reduction at genes associated with HSC maintenance. Altogether, these changes reinforce HSC self-renewal and diminish differentiation, paralleling phenotypic HSC aging behavior. Ribosomal biogenesis emerged as a particular target of aging with increased transcription of ribosomal protein and RNA genes and hypomethylation of rRNA genes. This data set will serve as a reference for future epigenomic analysis of stem cell aging.

%B Cell Stem Cell %V 14 %P 673-88 %8 2014 May 01 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/24792119?dopt=Abstract %R 10.1016/j.stem.2014.03.002 %0 Journal Article %J Nat Genet %D 2014 %T Large conserved domains of low DNA methylation maintained by Dnmt3a. %A Jeong, Mira %A Sun, Deqiang %A Luo, Min %A Huang, Yun %A Challen, Grant A %A Rodriguez, Benjamin %A Zhang, Xiaotian %A Chavez, Lukas %A Wang, Hui %A Hannah, Rebecca %A Kim, Sang-Bae %A Yang, Liubin %A Ko, Myunggon %A Chen, Rui %A Göttgens, Berthold %A Lee, Ju-Seog %A Gunaratne, Preethi %A Godley, Lucy A %A Darlington, Gretchen J %A Rao, Anjana %A Li, Wei %A Goodell, Margaret A %K 5-Methylcytosine %K Animals %K Base Sequence %K Conserved Sequence %K CpG Islands %K Cytosine %K Databases, Genetic %K DNA (Cytosine-5-)-Methyltransferases %K DNA Methylation %K DNA Methyltransferase 3A %K Epigenesis, Genetic %K Gene Expression Regulation %K Hematopoietic Stem Cells %K Histones %K Humans %K Leukemia %K Male %K Mice %K Mice, Inbred C57BL %K Mice, Mutant Strains %X

Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.

%B Nat Genet %V 46 %P 17-23 %8 2014 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/24270360?dopt=Abstract %R 10.1038/ng.2836