Identification of DNA methylation changes at<i>cis</i>-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulfite sequencing

Lipka, Daniel B.; Wang, Qi; Cabezas-Wallscheid, Nina; Klimmeck, Daniel; Weichenhan, Dieter; Herrmann, Carl; Lier, Amelie; Brocks, David; Paleske, Lisa von; Renders, Simon; Wünsche, Peer; Zeisberger, Petra; Gu, Lei; Haas, Simon; Essers, Marieke; Brors, Benedikt; Eils, Roland; Trumpp, Andreas; Milsom, Michael D.; Plass, Christoph

doi:10.4161/15384101.2014.973334

Cited by 37 publications

(31 citation statements)

References 75 publications

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“…Correlation of aberrantly methylated jmmlDMPs with the expression levels of corresponding genes across the JMML methylation subgroups demonstrated a trend towards inverse correlation of gene expression with DNA methylation, which is in line with previous findings for correlation of gene expression and DNA methylation in normal blood cell types ( Supplementary Fig. 6c) [29][30][31] . GSEA of the ranked gene list, revealed enrichment of genes known to be silenced by KRAS signaling as the only statistically significant hit ( Supplementary Fig.…”

Section: Dna Methylation Correlates With Clinical and Genetic Featuressupporting

confidence: 80%

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Lipka

Witte

Tóth

et al. 2017

Experimental Hematology

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Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative disorder of early childhood characterized by mutations activating RAS signaling. Established clinical and genetic markers fail to fully recapitulate the clinical and biological heterogeneity of this disease. Here we report DNA methylome analysis and mutation profiling of 167 JMML samples. We identify three JMML subgroups with unique molecular and clinical characteristics. The high methylation group (HM) is characterized by somatic PTPN11 mutations and poor clinical outcome. The low methylation group is enriched for somatic NRAS and CBL mutations, as well as for Noonan patients, and has a good prognosis. The intermediate methylation group (IM) shows enrichment for monosomy 7 and somatic KRAS mutations. Hypermethylation is associated with repressed chromatin, genes regulated by RAS signaling, frequent co-occurrence of RAS pathway mutations and upregulation of DNMT1 and DNMT3B, suggesting a link between activation of the DNA methylation machinery and mutational patterns in JMML.

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Section: Dna Methylation Correlates With Clinical and Genetic Featuressupporting

confidence: 80%

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Lipka

Witte

Tóth

et al. 2017

Experimental Hematology

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“…It is well known that methylation changes occurring in gene regulatory regions in a physiological or pathological context usually start from the borders of a given regulatory region and that is why one can generally observe the strongest methylation changes in CpG island shores but also in the distal regions of a given promoter or enhancer. 27,31 This effect is nicely recapitulated in Fig. 1A.…”

Section: Resultssupporting

confidence: 68%

“…The only exceptions are gene regulatory regions like enhancers and promoters that are associated with (potentially) active genes. 26,27 Gene regulatory regions are enriched for CpG islands, which are usually protected from methylation and thus can be found most frequently in the vicinity of constitutively active genes. All three AKAP12 isoforms are under the control of independent promoter regions, each containing one or more CpG islands.…”

Section: Resultsmentioning

confidence: 99%

“…This is of special interest, since both GATA2 expression and binding are tightly regulated epigenetically during early haematopoietic commitment. 26,27 Our motif search further identified an additional E-box predicted to bind the homeobox protein Nkx-2 that is located immediately 5 0 of the differentially methylated DNA stretch. An upstream stimulatory factor (USF) binding site was predicted 50 bp downstream of the hypermethylated region.…”

Section: Identification Of Potentially Disrupted Gene Regulatory Regimentioning

confidence: 98%

“…These data are well in line with published genome-wide data that show a global inverse correlation of DNA methylation dynamics with gene expression changes in the context of normal haematopoietic differentiation. 27 Since hyperactive RAS signaling is a hallmark of JMML, reexpression of the negative RAS signaling regulator AKAP12 could be one potential mechanism that might explain the treatment responses frequently observed in patients upon demethylating therapy. 1,35 In addition, HDAC-inhibition was also able to re-express AKAP12a, although this effect even under ongoing treatment was only transient if no DNMT-inhibitor was given concomitantly.…”

Section: Dna Methylation Of the Akap12a Promoter Correlates With Akapmentioning

confidence: 99%

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Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia

et al. 2016

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A-kinase anchor protein 12 (AKAP12) is a regulator of protein kinase A and protein kinase C signaling, acting downstream of RAS. Epigenetic silencing of AKAP12 has been demonstrated in different cancer entities and this has been linked to the process of tumorigenesis. Here, we used quantitative highresolution DNA methylation measurement by MassARRAY to investigate epigenetic regulation of all three AKAP12 promoters (i.e., a, b, and g) within a large cohort of juvenile myelomonocytic leukemia (JMML) patient samples. The AKAP12a promoter shows DNA hypermethylation in JMML samples, which is associated with decreased AKAP12a expression. Promoter methylation of AKAP12a correlates with older age at diagnosis, elevated levels of fetal hemoglobin and poor prognosis. In silico screening for transcription factor binding motifs around the sites of most pronounced methylation changes in the AKAP12a promoter revealed highly significant scores for GATA-2/-1 sequence motifs. Both transcription factors are known to be involved in the haematopoietic differentiation process. Methylation of a reporter construct containing this region resulted in strong suppression of AKAP12 promoter activity, suggesting that DNA methylation might be involved in the aberrant silencing of the AKAP12 promoter in JMML. Exposure to DNMT-and HDAC-inhibitors reactivates AKAP12a expression in vitro, which could potentially be a mechanism underlying clinical treatment responses upon demethylating therapy. Together, these data provide evidence for epigenetic silencing of AKAP12a in JMML and further emphasize the importance of dysregulated RAS signaling in JMML pathogenesis.

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The DNA methylation landscape of hematological malignancies: an update

2020

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The rapid advances in high‐throughput sequencing technologies have made it more evident that epigenetic modifications orchestrate a plethora of complex biological processes. During the last decade, we have gained significant knowledge about a wide range of epigenetic changes that crucially contribute to some of the most aggressive forms of leukemia, lymphoma, and myelodysplastic syndromes. DNA methylation is a key epigenetic player in the abnormal initiation, development, and progression of these malignancies, often acting in synergy with other epigenetic alterations. It also contributes to the acquisition of drug resistance. In this review, we summarize the role of DNA methylation in hematological malignancies described in the current literature. We discuss in detail the dual role of DNA methylation in normal and aberrant hematopoiesis, as well as the involvement of this type of epigenetic change in other aspects of the disease. Finally, we present a comprehensive overview of the main clinical implications, including a discussion of the therapeutic strategies that regulate or reverse aberrant DNA methylation patterns in hematological malignancies, including their combination with (chemo)immunotherapy.

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Identification of DNA methylation changes atcis-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulfite sequencing

Abstract: (2014) Identification of DNA methylation changes at cis-regulatory elements during early steps of HSC differentiation using tagmentation-based whole genome bisulfite sequencing, Cell Cycle, 13:22, 3476-3487,

Cited by 37 publications

References 75 publications

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Ras-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia

Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia

The DNA methylation landscape of hematological malignancies: an update

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