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Tissue-specific DNA demethylation is required for proper B-cell differentiation and function

Published on May 3, 2016in Proceedings of the National Academy of Sciences of the United States of America9.58
· DOI :10.1073/pnas.1604365113
Shari Orlanski6
Estimated H-index: 6
(HUJI: Hebrew University of Jerusalem),
Verena Labi22
Estimated H-index: 22
+ 8 AuthorsYehudit Bergman37
Estimated H-index: 37
(HUJI: Hebrew University of Jerusalem)
Sources
Abstract
There is ample evidence that somatic cell differentiation during development is accompanied by extensive DNA demethylation of specific sites that vary between cell types. Although the mechanism of this process has not yet been elucidated, it is likely to involve the conversion of 5mC to 5hmC by Tet enzymes. We show that a Tet2/Tet3 conditional knockout at early stages of B-cell development largely prevents lineage-specific programmed demethylation events. This lack of demethylation affects the expression of nearby B-cell lineage genes by impairing enhancer activity, thus causing defects in B-cell differentiation and function. Thus, tissue-specific DNA demethylation appears to be necessary for proper somatic cell development in vivo.
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  • Citations (36)
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References69
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#1Zhigang Zhao (IU: Indiana University)H-Index: 3
#2Li Chen (Emory University)H-Index: 17
Last. Mingjiang Xu (IU: Indiana University)H-Index: 35
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Summary TET1/2/3 are methylcytosine dioxygenases that regulate cytosine hydroxymethylation. Tet1/2 are abundantly expressed in HSC/HPCs and are implicated in hematological malignancies. Tet2 deletion in mice causes myeloid malignancies, while Tet1 - null mice develop B cell lymphoma after an extended period of latency. Interestingly, TET1/2 are often concomitantly downregulated in acute B-lymphocytic leukemia. Here, we investigated the overlapping and non-redundant functions of Tet1/2 using Tet1...
43 CitationsSource
#1Pilar M. Dominguez (Cornell University)H-Index: 9
#2Matt Teater (Cornell University)H-Index: 13
Last. Rita Shaknovich (Cornell University)H-Index: 37
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Summary Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wild-type (WT) and AID-deficient ( Aicda −/− ) mice. We determined that the transit of B cells t...
42 CitationsSource
#1Claudia Bossen (UCSD: University of California, San Diego)H-Index: 6
#2Caroline S. Murre (UCSD: University of California, San Diego)H-Index: 3
Last. Cornelis Murre (UCSD: University of California, San Diego)H-Index: 73
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B lineage development requires the transcription factors E2A, EBF1, Foxo1 and Ikaros. Murre and colleagues show that these factors gain access to lineage-specific enhancer sites by the action of the chromatin remodeler Brg1.
47 CitationsSource
#1Marta KulisH-Index: 18
#2Angelika MerkelH-Index: 17
Last. José I. Martín-SuberoH-Index: 88
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Jose Martin-Subero and colleagues report the whole-genome bisulfite sequencing of ten blood cell subpopulations representing the cellular stages during B cell differentiation. They find that early stages are characterized by enhancer demethylation and that neoplasms derived from B cell lineages undergo methylation changes in regions with dynamic methylation during normal differentiation.
122 CitationsSource
#1Timothy H. Bestor (Columbia University)H-Index: 62
#2John R. Edwards (WashU: Washington University in St. Louis)H-Index: 28
Last. Mathieu Boulard (Columbia University)H-Index: 5
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It has been nearly 40 y since it was suggested that genomic methylation patterns could be transmitted via maintenance methylation during S phase and might play a role in the dynamic regulation of gene expression during development [Holliday R, Pugh JE (1975) Science 187(4173):226–232; Riggs AD (1975) Cytogenet Cell Genet 14(1):9–25]. This revolutionary proposal was justified by “... our almost complete ignorance of the mechanism for the unfolding of the genetic program during development” that p...
107 CitationsSource
#1Luisa Cimmino (NYU: New York University)H-Index: 15
#2Meelad M. Dawlaty (MIT: Massachusetts Institute of Technology)H-Index: 20
Last. Iannis Aifantis (NYU: New York University)H-Index: 52
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Methylation of DNA CpG motifs is modulated in part by the TET family of epigenetic regulators. Aifantis and colleagues show that loss of TET1 function biases hematopoiesis toward the B cell lineage and promotes hematopoietic malignancies.
90 CitationsSource
#1Kasper D. Rasmussen (UCPH: University of Copenhagen)H-Index: 10
#2Guangshuai Jia (UCPH: University of Copenhagen)H-Index: 1
Last. Kristian Helin (UCPH: University of Copenhagen)H-Index: 98
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DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles a...
94 CitationsSource
#1Yitzhak Reizel (HUJI: Hebrew University of Jerusalem)H-Index: 3
#2Adam Spiro (Weizmann Institute of Science)H-Index: 8
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DNA methylation patterns are set up in a relatively fixed programmed manner during normal embryonic development and are then stably maintained. Using genome-wide analysis, we discovered a postnatal pathway involving gender-specific demethylation that occurs exclusively in the male liver. This demodification is programmed to take place at tissue-specific enhancer sequences, and our data show that the methylation state at these loci is associated with and appears to play a role in the transcriptio...
28 CitationsSource
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Summary Specific combinations of acute myeloid leukemia (AML) disease alleles, including FLT3 and TET2 mutations, confer distinct biologic features and adverse outcome. We generated mice with mutations in Tet2 and Flt3 , which resulted in fully penetrant, lethal AML. Multipotent Tet2 −/− ;Flt3 ITD progenitors (LSK CD48 + CD150 − ) propagate disease in secondary recipients and were refractory to standard AML chemotherapy and FLT3-targeted therapy. Flt3 ITD mutations and Tet2 loss cooperatively re...
95 CitationsSource
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DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting and X-chromosome inactivation. Cancer cells display highly dysregulated DNA methylation profiles characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands (CGIs) that presumably lead to genome instability and aberrant expression of tumor suppressor genes or oncogenes. The recent discovery of Ten-Eleven-Translocation (TET) family dioxygena...
89 CitationsSource
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