Modifications of H3K4 methylation levels are associated with DNA hypermethylation in acute myeloid leukemia

Abstract

The ‘instructive model’ of aberrant DNA methylation in human tumors is based on the observation that CpG islands prone to hypermethylation in cancers are embedded in chromatin enriched in H3K27me3 in human embryonic stem cells (hESC). Recent studies also link methylation of CpG islands to the methylation status of H3K4, where H3K4me3 is inversely correlated with DNA methylation. To provide insight into these conflicting findings, we generated DNA methylation profiles for acute myeloid leukemia samples from patients and leukemic cell lines and integrated them with publicly available ChIp‐seq data, containing H3K4me3 and H3K27me3 CpG island occupation in hESC, or hematopoietic stem or progenitor cells (hHSC/MPP). Hypermethylated CpG islands in AML samples displayed H3K27me3 enrichments in hESC and hHSC/MPP; however, ChIp analysis of specific hypermethylated CpG islands revealed a significant reduction in H3K4me3 signal with a concomitant increase in H3K4me0 levels as opposed to a nonsignificant increase in H3K27me3 marks. The integration of AML DNA methylation profiles with the ChIp‐seq data in hESC and hHSC/MPP also led to the identification of Iroquois homeobox 2 (IRX2) as a previously unknown factor promoting differentiation of leukemic cells. Our results indicate that in contrast to the ‘instructive model’, H3K4me3 levels are strongly associated with DNA methylation patterns in AML and have a role in the regulation of critical genes, such as the putative tumor suppressor IRX2.

The Hematopoietic TALE-Code Shows Normal Activity of IRX1 in Myeloid Progenitors and Reveals Ectopic Expression of IRX3 and IRX5 in Acute Myeloid Leukemia

“…The deregulated activity of IRX genes in AML has been reported in previous studies as well. Accordingly, the aberrant expression of IRX1 plays an oncogenic role in cases with particular MLL rearrangements, and IRX3 inhibits myelomonocytic differentiation, while IRX2 supports myeloid differentiation [ 13 , 14 , 40 ]. Thus, the published results together with our data indicate functional differences between IRX factors in AML.…”

Distinct Associations of BMI and Fatty Acids With DNA Methylation in Fasting and Postprandial States in Men

“…Ow-dmCpG mapped to a number of genes involved in obesity and metabolism. Notable examples were MAP4K2 or GCK, close to an SNP associated with uric acid and a candidate player in inflammation (Chuang et al, 2016;Lee et al, 2018); IRX2, associated with BMI in women and expressed in an adipose tissue depotdependent fashion (Karastergiou et al, 2013;Ng et al, 2017)-IRX2 promotes cellular differentiation in leukemia and could therefore exert currently unappreciated obesity-related effects in blood cells, for instance by altering the leukocyte repertoire (Scalea et al, 2020); KLF3, a driver of diet-induced obesity in mice which could act by promoting the expression of the adipose browning factor in selected white blood cells (Bell-Anderson et al, 2013;Knights et al, 2020); RREB1, promoting adipose tissue browning (Brunmeir et al, 2016)the RREB1-altered expression in peripheral blood is associated with pediatric obesity (Plaza-Florido et al, 2020); KLHL32, associated with BMI in a blood-based genome-wide association study (Monda et al, 2013); PLOD3 (aka LH3), involved in adiponectin production (Zhang et al, 2015)-peripheral blood PLOD3 expression is altered in obstructive sleep apnea, a condition linked to obesity (Perry et al, 2013); and HVCN1, a driver of reactive oxygen species production in B cells (Capasso et al, 2010). The most significant enrichment was of targets for E47, an activator of adiponectin expression (Doran et al, 2008).…”

The Role of H3K4 Trimethylation in CpG Islands Hypermethylation in Cancer

“…However, there is no evidence that an H3K4me3's protective effect against aberrant methylation exists or is lost in tumors. Our studies [214] conducted on an acute myeloid leukemia cancer model suggest a direct role of the deregulation of H3K4me3 levels in determining the hypermethylation of the corresponding CGI.…”