Directional DNA Methylation Changes and Complex Intermediate States Accompany Lineage Specificity in the Adult Hematopoietic Compartment

Watson School of Biological Sciences, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Molecular cell (Impact Factor: 14.02). 09/2011; 44(1):17-28. DOI: 10.1016/j.molcel.2011.08.026
Source: PubMed


DNA methylation has been implicated as an epigenetic component of mechanisms that stabilize cell-fate decisions. Here, we have characterized the methylomes of human female hematopoietic stem/progenitor cells (HSPCs) and mature cells from the myeloid and lymphoid lineages. Hypomethylated regions (HMRs) associated with lineage-specific genes were often methylated in the opposing lineage. In HSPCs, these sites tended to show intermediate, complex patterns that resolve to uniformity upon differentiation, by increased or decreased methylation. Promoter HMRs shared across diverse cell types typically display a constitutive core that expands and contracts in a lineage-specific manner to fine-tune the expression of associated genes. Many newly identified intergenic HMRs, both constitutive and lineage specific, were enriched for factor binding sites with an implied role in genome organization and regulation of gene expression, respectively. Overall, our studies represent an important reference data set and provide insights into directional changes in DNA methylation as cells adopt terminal fates.

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    • "Together, these data suggest that altered DNA methylation may play a role in underwriting the functional decline associated with stem cell aging in these tissues. In recent years, numerous studies have demonstrated that unique DNA methylation marks are established as adult stem cells undergo differentiation (Hodges et al., 2011; Ji et al., 2010; Bock et al., 2012; Kaaij et al., 2013), suggesting that de novo methylation is critical for stem cell differentiation. Indeed, impaired differentiation is seen in postnatal Dnmt3a knockout mouse NSCs (Wu et al., 2010). "
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    ABSTRACT: Stem cell decline is an important cellular driver of aging-associated pathophysiology in multiple tissues. Epigenetic regulation is central to establishing and maintaining stem cell function, and emerging evidence indicates that epigenetic dysregulation contributes to the altered potential of stem cells during aging. Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self; alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated and amplified within the stem cell pool through self-renewal divisions. This Review focuses on recent studies examining epigenetic regulation of tissue-specific stem cells in homeostasis, aging, and aging-related disease. Copyright © 2015 Elsevier Inc. All rights reserved.
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    • "In addition, these oxidated bases are recognized by the base-excision repair (BER) pathway and catalytically removed. binding sites compared to the rest of the genome (Hodges et al., 2011; Stadler et al., 2011; Hogart et al., 2012; Oda et al., 2013; Feldmann et al., 2013; Ziller et al., 2013). This recurrent observation obviously pointed to a function of transcription factor binding events in causing these changes in the DNA methylation profile. "
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    • "Aging-Associated DNA Methylation Interferes with the Transcriptional Network Previous DNA methylation studies showed that hypomethylated regions are usually associated with cell-specific regulatory regions or TF binding sites (Hodges et al., 2011; Stadler et al., 2011; Ziller et al., 2013). To determine whether the methylation states in such regulatory regions change with HSC aging, we examined the methylation ratio in the binding sites of five TFs associated with HSC pluripotency, including Scl, Erg, Gata2, Runx1, and Ldb1 (Wilson et al., 2010). "

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