MIR retrotransposons link the epigenome and the transcriptome of coding genes in acute myeloid leukemia

Abstract

DNMT3A and IDH1/2 mutations combinatorically regulate the transcriptome and the epigenome in acute myeloid leukemia; yet the mechanisms of this interplay are unknown. Using a systems approach within topologically associating domains, we find that genes with significant expression-methylation correlations are enriched in signaling and metabolic pathways. The common denominator across these methylation-regulated genes is the density in MIR retrotransposons of their introns. Moreover, a discrete number of CpGs overlapping enhancers are responsible for regulating most of these genes. Established mouse models recapitulate the dependency of MIR-rich genes on the balanced expression of epigenetic modifiers, while projection of leukemic profiles onto normal hematopoiesis ones further consolidates the dependencies of methylation-regulated genes on MIRs. Collectively, MIR elements on genes and enhancers are susceptible to changes in DNA methylation activity and explain the cooperativity of proteins in this pathway in normal and malignant hematopoiesis.

MPN Transformation Is Characterized By Heterogeneous Shifts In Lineage Character Resulting In Both HSC-Like And More Differentiated Lineage Signatures

“…To our knowledge, this is the first description of the transcriptional characteristics of MPN-AP/BP, its comparison to de novo AML, and the first paired comparison of transcriptional and lineage characteristics for patients with chronic-phase MPNs that subsequently transformed. Our study provides valuable insights into the transcriptomic landscape of transformed MPNs (including both accelerated-and blast-phase disease), and builds on prior insights derived from de novo AML [26][27][28][29][30] . By leveraging an integrated analysis with the BeatAML cohort, we are able to draw novel contrasts to de novo AML, including distinct characteristics and quantification of poor outcomes in patients with high-risk transformed MPNs.…”

Research Progress on the Role of Epigenetic Methylation Modification in Hepatocellular Carcinoma

“… 30 MIR elements in genes and enhancers, sensitive to changes in DNA methylation activity, are implicated in hematological cancers. 88 Currently, the DNA methylation of other regions of these genes in HCC remains an area for further study.…”