Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity

Schmidl, Christian; Klug, Maja; Boeld, Tina J.; Andreesen, Reinhard; Hoffmann, Petra; Edinger, Matthias; Rehli, Michael

doi:10.1101/gr.091470.109

Cited by 208 publications

(205 citation statements)

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“…In some cancers, methylation of tumor suppressor gene promoters is associated with gene repression (6) lending support to the suggestion that CpG methylation is a general repressive epigenetic mark (7). CpG methylation patterns are not as dynamic as previously thought (8), and it is mainly the regions outside of proximal promoters that become demethylated upon cellular differentiation (9)(10)(11). Genomic analyses have identified low CpG promoters that are both methylated and transcriptionally active (8,12), but the mechanism underlying the activation of methylated promoters remains unclear.…”

mentioning

confidence: 70%

CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes

Rishi

Bhattacharya

Chatterjee

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

208

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DNA methylation of the cytosine in the CpG dinucleotide is typically associated with gene silencing. Genomic analyses have identified low CpG promoters that are both methylated and transcriptionally active, but the mechanism underlying the activation of these methylated promoters remains unclear. Here we show that CpG methylation of the CRE sequence (TGACGTCA) enhances the DNA binding of the C/EBPα transcription factor, a protein critical for activation of differentiation in various cell types. Transfection assays also show that C/EBPα activates the CRE sequence only when it is methylated. The biological significance of this observation was seen in differentiating primary keratinocyte cultures from newborn mice where certain methylated promoters are both bound by C/EBPα and activated upon differentiation. Experimental demethylation by either 5-azacytidine treatment or DNMT1 depletion diminished both C/EBPα binding and activation of the same methylated promoters upon differentiation suggesting that CpG methylation can localize C/EBPα. Transfection studies in cell cultures using methylated tissue-specific proximal promoters identified half-CRE (CGTCA) and half-C/EBP (CGCAA) sequences that need to be methylated for C/EBPα mediated activation. In primary dermal fibroblasts, C/EBPα activates a different set of methylated tissue-specific promoters upon differentiation into adipocytes. These data identify a new function for methyl CpGs: producing DNA binding sites at half-CRE and half-C/EBP sequences for C/EBPα that are needed to activate tissue-specific genes.

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mentioning

confidence: 70%

CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes

Rishi

Bhattacharya

Chatterjee

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

208

251

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“…One explanation for this finding is that the right and left colon arise from different embryological sources (midgut vs. hindgut) and it has been shown previously that alterations in methylation of the CpG islands located remotely from promoters and transcription start sites is frequently associated with particular tissue types and cell lineages. [34][35][36] We anticipate that the results of these studies will help inform the development of epigenetic biomarkers from the normal colon that are reflective of a "field cancerization process." An understanding of epigenetic variability in the normal colon, where no neoplasia exists, is a prerequisite to determining whether particular alterations in DNA methylation are genuine markers of a field effect and not merely reflective of a predictable degree of variability related to colon site, patient age, environmental factors, and so forth.…”

Section: Discussionmentioning

confidence: 99%

Patterns of DNA methylation in the normal colon vary by anatomical location, gender, and age

et al. 2014

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“…1 Cell type-specific epigenetic signatures are particularly evident at promoter-distal sites, where histone H3K4 monomethylation/dimethylation, 2,3 histone H3K27 acetylation, 3,4 the histone variant H2AZ, 2 or DNA demethylation 5,6 indicate the presence of poised or activated lineage-specific enhancer elements. These distal regulatory elements are often cell type-specific, are correlated with gene expression, and are bound by combinations of common and cell type-specific key regulators.…”

Section: Introductionmentioning

confidence: 99%

Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states

Pham

Benner

Lichtinger

et al. 2012

Blood

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Cellular differentiation is orchestrated by lineage-specific transcription factors and associated with cell type-specific epigenetic signatures. In the present study, we used stage-specific, epigenetic "fingerprints" to deduce key transcriptional regulators of the human monocytic differentiation process. We globally mapped the distribution of epigenetic enhancer marks (histone H3 lysine 4 monomethylation, histone H3 lysine 27 acetylation, and the histone variant H2AZ), describe general properties of marked regions, and show that cell type-specific epigenetic "fingerprints" are correlated with specific, de novo-derived motif signatures at all of the differentiation stages studied (ie, hematopoietic stem cells, monocytes, and macrophages). We validated the novel, de novo-derived, macrophage-specific enhancer signature, which included ETS, CEBP, bZIP, EGR, E-Box and NF-B motifs, by ChIP sequencing for a subset of motif corresponding transcription factors (PU.1, C/EBP␤, and EGR2), confirming their association with differentiationassociated epigenetic changes. We describe herein the dynamic enhancer landscape of human macrophage differentiation, highlight the power of genome-wide epigenetic profiling studies to reveal novel functional insights, and provide a unique resource for macrophage biologists. IntroductionHuman monocyte-to-macrophage differentiation is a process involving marked morphologic, functional, and transcriptional changes that proceed in the absence of proliferation. The mechanisms controlling this transition are not well understood on the molecular level, in part because both human monocytes and macrophages are hard to manipulate without triggering defense programs that interfere with normal differentiation.Recent global epigenetic and transcription factor profiling studies in various cell types have provided ample evidence for a tight relationship between transcription factor binding and the local deposition/removal of some epigenetic marks, including histone methylation or acetylation, the appearance of histone variants, or DNA demethylation. 1 Cell type-specific epigenetic signatures are particularly evident at promoter-distal sites, where histone H3K4 monomethylation/dimethylation, 2,3 histone H3K27 acetylation, 3,4 the histone variant H2AZ, 2 or DNA demethylation 5,6 indicate the presence of poised or activated lineage-specific enhancer elements. These distal regulatory elements are often cell type-specific, are correlated with gene expression, and are bound by combinations of common and cell type-specific key regulators. 1,7 For example, in the murine hematopoietic system, macrophage-specific putative enhancer elements are characterized by PU.1, C/EBP␣/␤, and AP-1 binding, whereas putative enhancer elements in a related blood-cell type (murine B cells) that are also characterized by PU.1 binding associate with a distinct set of B cell-specific factors, including E2A, EBF, and OCT2. 8 Observations of correlating transcription factor binding and epigenetic patterns were also made in other cellul...

show abstract

Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity

Cited by 208 publications

References 50 publications

CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes

CpG methylation of half-CRE sequences creates C/EBPα binding sites that activate some tissue-specific genes

Patterns of DNA methylation in the normal colon vary by anatomical location, gender, and age

Dynamic epigenetic enhancer signatures reveal key transcription factors associated with monocytic differentiation states

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