Title : Fusion protein driven 3D transcriptional network in acute myeloid leukemia
Diseases are underpinned by an altered gene expression profile, which is directed by changes in the regulatory chromatin interaction landscape. Understanding how the physical contacts between regulatory elements and promoters are dysregulated helps to elucidate the disease mechanism. Recent chromatin conformation capture methods allow for studying chromatin interactions at high resolution, and are able to resolve regulatory promoter-enhancer contacts. We applied promoter capture Hi-C, a technique that targets long-range interactions of promoters, to identify chromatin loops specific to acute myeloid leukemia (AML) subtypes.
AML is a prevalent disease with several genetically defined subtypes. In most AML subtypes, leukemogenesis is driven by a single translocation in the presence of only a few additional mutations. These translocations commonly generate fusion proteins that exhibit distinct binding patterns compared to either of the wild type proteins. Here, we studied patient samples carrying translocations involving the KMT2A gene on chr11, encoding for the histone methyltransferase mixed-lineage leukemia 1 (MLL1). Translocations with different partners confer prognoses ranging from intermediate to poor. The studied patients had translocation partners on chr6 and chr9, with poor and intermediate prognosis, respectively.
We found that thousands of promoters show differences in their regulatory interactions compared to CD34+ hematopoietic stem cells. The genes with altered regulation are enriched for genes known to be involved in leukemic transformation and disease progression. For a subset of these genes we observed marked differences depending on the translocation partner, which imply that differences in the regulatory contact might contribute to different patient outcomes. Most strikingly, we found in AML patient samples a strong interchromosomal network of fusion protein target genes, pointing at the importance of the fusion proteins in the general orchestration of chromatin folding.
Audience Take Away:
- Audience will learn about the role of chromatin organization in epigenetic regulation of gene expression.
- It will introduce the promoter capture Hi-C technique in detail, which can be used in studying gene regulation in other diseases as well.
- Will show that epigenetic differences can lead to differences in patient outcome, and therefore are important to assess for the purpose of precision medicine.