BackgroundCancers have long been recognized to be not only genetically but also epigenetically distinct from their tissues of origin. Although genetic alterations underlying oncogene upregulation have been well studied, to what extent epigenetic mechanisms, such as DNA methylation, can also induce oncogene expression remains unknown.ResultsHere, through pan-cancer analysis of 4174 genome-wide profiles, including whole-genome bisulfite sequencing data from 30 normal tissues and 35 solid tumors, we discover a strong correlation between gene-body hypermethylation of DNA methylation canyons, defined as broad under-methylated regions, and overexpression of approximately 43% of homeobox genes, many of which are also oncogenes. To gain insights into the cause-and-effect relationship, we use a newly developed dCas9-SunTag-DNMT3A system to methylate genomic sites of interest. The locus-specific hypermethylation of gene-body canyon, but not promoter, of homeobox oncogene DLX1, can directly increase its gene expression.ConclusionsOur pan-cancer analysis followed by functional validation reveals DNA hypermethylation as a novel epigenetic mechanism for homeobox oncogene upregulation.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1492-3) contains supplementary material, which is available to authorized users.

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression lead to leukemogenic transformation. Here, for the first time, we comprehensively prove NPM1c binds to a subset of active gene promoters in NPM1c AMLs, including well-known leukemia-driving genes – HOXA/B cluster genes and MEIS1. NPM1c sustains the active transcription of key target genes by orchestrating a transcription hub and maintains the active chromatin landscape by inhibiting the activity of histone deacetylases (HDACs). Together, these findings reveal the neomorphic function of NPM1c as a transcriptional amplifier for leukemic gene expression and open up new paradigms for therapeutic intervention.

Genome-wide transcriptome studies have identified thousands of long intergenic noncoding RNAs (lincRNAs), some of which play important roles in pre-implantation embryonic development (PED). Pig is an ideal model for reproduction, however, porcine lincRNAs are still poorly characterized and it is unknown if they are associated with porcine PED. Here we reconstructed 195,531 transcripts in 122,007 loci, and identified 7,618 novel lincRNAs from 4,776 loci based on published RNA-seq data. These lincRNAs show low exon number, short length, low expression level, tissue-specific expression and cis-acting, which is consistent with previous reports in other species. By weighted co-expression network analysis, we identified 5 developmental stages specific co-expression modules. Gene ontology enrichment analysis of these specific co-expression modules suggested that many lincRNAs are associated with cell cycle regulation, transcription and metabolism to regulate the process of zygotic genome activation. Futhermore, we identified hub lincRNAs in each co-expression modules, and found two lincRNAs TCONS_00166370 and TCONS_00020255 may play a vital role in porcine PED. This study systematically analyze lincRNAs in pig and provides the first catalog of lincRNAs that might function as gene regulatory factors of porcine PED.

<p>Supplementary Figure S1 is associated with Figure1 and it shows the NPM1-WT binds to the rDNA arrays and NPM1c binds to non-repetitive genomic regions. Supplementary Figure S2 is associated with Figure1 and it shows NPM1c’s chromatin binding and association with gene expression. Supplementary Figure S3 is associated with Figure2 and shows NPM1c regulates the transcription of its target genes with BRU-seq. Supplementary Figure S4 is associated with Figure2 and it shows the characterization of NPM1c condensate with biochemical assay and imaging assay. Supplementary Figure S5 is associated with figure 3. The figure shows NPM1c and chromatin landacpe dymanics during dTag-13 treatment and wash-off. Supplementary Figure S6 is associated with figure 4. It shows the supplemental data of HOXB8-NPM1c-knock-in model. Supplementary figure S7 is associated with figure 5. It shows the supplemental data of XPO1's binding to chromatin in various leukemia cell lines and normal HSPCs. Supplementary Figure S8 is associated with figure 6. It shows the supplemental information of synergy between Menin and XPO1 inhibitor in the NPM1c AML cell line model.</p>

<p>Supplementary Table S1 shows the high-confident NPM1c binding peaks in OCI-AML3 cells.</p>